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Congenital Heart Defect v0.430 HYAL2 Zornitza Stark Phenotypes for gene: HYAL2 were changed from Cleft lip and palate; cor triatriatum; congenital cardiac malformations to Muggenthaler-Chowdhury-Chioza syndrome, MIM# 621063
Congenital Heart Defect v0.429 HYAL2 Zornitza Stark reviewed gene: HYAL2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Muggenthaler-Chowdhury-Chioza syndrome, MIM# 621063; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.429 RBFOX2 Ain Roesley Phenotypes for gene: RBFOX2 were changed from RBFOX2-related congenital heart disorder (MONDO:0100557) to RBFOX2-related congenital heart disorder (MONDO:0100557)
Congenital Heart Defect v0.428 RBFOX2 Ain Roesley Phenotypes for gene: RBFOX2 were changed from Congenital heart disease MONDO:0005453, RBFOX2-related to RBFOX2-related congenital heart disorder (MONDO:0100557)
Congenital Heart Defect v0.427 RBFOX2 Zornitza Stark Phenotypes for gene: RBFOX2 were changed from Hypoplastic left heart syndrome (HLHS) MONDO:0004933 to Congenital heart disease MONDO:0005453, RBFOX2-related
Congenital Heart Defect v0.426 RBFOX2 Zornitza Stark Classified gene: RBFOX2 as Green List (high evidence)
Congenital Heart Defect v0.426 RBFOX2 Zornitza Stark Gene: rbfox2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.425 RBFOX2 Zornitza Stark edited their review of gene: RBFOX2: Added comment: STRONG by ClinGen. At least 5 unrelated families and supportive zebrafish model.; Changed rating: GREEN; Changed phenotypes: Congenital heart disease MONDO:0005453, RBFOX2-related
Congenital Heart Defect v0.425 FRYL Zornitza Stark Marked gene: FRYL as ready
Congenital Heart Defect v0.425 FRYL Zornitza Stark Gene: fryl has been classified as Green List (High Evidence).
Congenital Heart Defect v0.425 FRYL Zornitza Stark Phenotypes for gene: FRYL were changed from neurodevelopmental disorder MONDO:0700092, FRYL-related to Pan-Chung-Bellen syndrome, MIM# 621049
Congenital Heart Defect v0.424 FRYL Zornitza Stark reviewed gene: FRYL: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pan-Chung-Bellen syndrome, MIM# 621049; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.424 WDR47 Bryony Thompson Marked gene: WDR47 as ready
Congenital Heart Defect v0.424 WDR47 Bryony Thompson Gene: wdr47 has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.424 WDR47 Bryony Thompson gene: WDR47 was added
gene: WDR47 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: WDR47 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WDR47 were set to 35474353; 39609633
Phenotypes for gene: WDR47 were set to Congenital heart disease MONDO:0005453
Review for gene: WDR47 was set to RED
Added comment: A rare assumed de novo heterozygous variant (NM_014969.5:c.2056G>A p.(Val686Ile) - 10 hets in gnomAD v4.1) detected in a case with heterotaxy including AVCD, vena azygos continuation, artery lusoria, truncus bicaroticus and polysplenia. Screening of exams for 2,019 individuals with situs inversus totalis, heterotaxy, or isolated CHD detected 2 additional individuals with monoallelic rare missense variants. No functional assays or other supporting evidence. All variants are VUS. In a recent publication of biallelic variants associated with a complex neurodevelopmental syndrome, heterozygous carriers had no phenotype.
Sources: Literature
Congenital Heart Defect v0.423 FGF8 Zornitza Stark Marked gene: FGF8 as ready
Congenital Heart Defect v0.423 FGF8 Zornitza Stark Gene: fgf8 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.423 FGF8 Zornitza Stark Classified gene: FGF8 as Amber List (moderate evidence)
Congenital Heart Defect v0.423 FGF8 Zornitza Stark Gene: fgf8 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.422 FGF8 Zornitza Stark gene: FGF8 was added
gene: FGF8 was added to Congenital Heart Defect. Sources: Expert list
Mode of inheritance for gene: FGF8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FGF8 were set to 32664970; 7768185; 32664970; 10603341; 19509466; 9462741; 10603341; 12223415
Phenotypes for gene: FGF8 were set to Congenital heart disease MONDO:0005453, FGF8-related
Review for gene: FGF8 was set to AMBER
Added comment: Two individuals reported but extensive functional data. MODERATE by ClinGen.
Sources: Expert list
Congenital Heart Defect v0.421 ROCK2 Bryony Thompson Marked gene: ROCK2 as ready
Congenital Heart Defect v0.421 ROCK2 Bryony Thompson Gene: rock2 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.421 ROCK2 Bryony Thompson Classified gene: ROCK2 as Amber List (moderate evidence)
Congenital Heart Defect v0.421 ROCK2 Bryony Thompson Gene: rock2 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.420 ROCK2 Sangavi Sivagnanasundram gene: ROCK2 was added
gene: ROCK2 was added to Congenital Heart Defect. Sources: ClinGen
Mode of inheritance for gene: ROCK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ROCK2 were set to 28554332, 30622330, 31941532
Phenotypes for gene: ROCK2 were set to congenital heart disease MONDO:0005453
Review for gene: ROCK2 was set to AMBER
Added comment: Reported in 4 unrelated individuals however classified as LIMITED by ClinGen Congenital Heart Disease GCEP on 03/09/2024 - https://search.clinicalgenome.org/CCID:008432
Sources: ClinGen
Congenital Heart Defect v0.420 ZNRF3 Bryony Thompson Marked gene: ZNRF3 as ready
Congenital Heart Defect v0.420 ZNRF3 Bryony Thompson Gene: znrf3 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.420 ZNRF3 Bryony Thompson Classified gene: ZNRF3 as Amber List (moderate evidence)
Congenital Heart Defect v0.420 ZNRF3 Bryony Thompson Gene: znrf3 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.419 ZNRF3 Bryony Thompson gene: ZNRF3 was added
gene: ZNRF3 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: ZNRF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNRF3 were set to 39168120
Phenotypes for gene: ZNRF3 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: ZNRF3 was set to AMBER
Added comment: 12 individuals with ZNRF3 variants and various phenotypes. 8 individuals with de novo missense and neurodevelopment disorders (NDD), including cluster of variants in the RING ligase domain with macrocephalic NDD. Plus 4 individuals from 3 families with de novo truncating or de novo/inherited large in-frame deletion variants with non-NDD phenotypes, including heart, adrenal, or nephrotic problems. Overall, 4 individuals had congenital heart defects and 2 had microcephaly. Also, supporting in vitro functional assays.
Sources: Literature
Congenital Heart Defect v0.418 ALDH1A2 Gina Ravenscroft commented on gene: ALDH1A2
Congenital Heart Defect v0.418 TTC25 Zornitza Stark Tag new gene name tag was added to gene: TTC25.
Congenital Heart Defect v0.418 BMP2 Ain Roesley Marked gene: BMP2 as ready
Congenital Heart Defect v0.418 BMP2 Ain Roesley Gene: bmp2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.418 BMP2 Ain Roesley reviewed gene: BMP2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37572998, 29198724; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Congenital Heart Defect v0.418 BMP2 Ain Roesley Deleted their review
Congenital Heart Defect v0.418 BMP2 Ain Roesley Deleted their comment
Congenital Heart Defect v0.418 BMP2 Ain Roesley Classified gene: BMP2 as Green List (high evidence)
Congenital Heart Defect v0.418 BMP2 Ain Roesley Gene: bmp2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.417 BMP2 Ain Roesley gene: BMP2 was added
gene: BMP2 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: BMP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BMP2 were set to 29198724
Phenotypes for gene: BMP2 were set to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 1, MIM# 617877
Review for gene: BMP2 was set to GREEN
gene: BMP2 was marked as current diagnostic
Added comment: 8 families with 12 affecteds

4 with CHD
Transposition of the great arteries HP:0001669
Mild pulmonary valve stenosis HP:0001642
Ebstein's anomaly HP:0010316
Wolff-Parkinson-White syndrome HP:0001716, perimembranous VSD HP:0011682
Sources: Literature
Congenital Heart Defect v0.416 FRYL Ain Roesley Classified gene: FRYL as Green List (high evidence)
Congenital Heart Defect v0.416 FRYL Ain Roesley Gene: fryl has been classified as Green List (High Evidence).
Congenital Heart Defect v0.415 FRYL Ain Roesley gene: FRYL was added
gene: FRYL was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: FRYL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FRYL were set to 38479391
Phenotypes for gene: FRYL were set to neurodevelopmental disorder MONDO:0700092, FRYL-related
Review for gene: FRYL was set to GREEN
gene: FRYL was marked as current diagnostic
Added comment: 14 individuals, all de novo except 1x duo testing (not present in tested father)
5x missense + 8x fs/stopgain + 1x canonical splice

13/13 with ID/DD (1x deceased)
4/14 seizures
7/14 with cardiac anomalies such as PDA, TOF, VSD, dextrocardia

1x also has a de novo fs variant in SF3B4
1x also has a de novo stop gain variant in SDHA

functional studies using flies were performed
Sources: Literature
Congenital Heart Defect v0.414 RBFOX2 Ain Roesley Publications for gene: RBFOX2 were set to 26785492; 27670201; 27485310; 25205790; 35137168; 26785492
Congenital Heart Defect v0.413 RBFOX2 Ain Roesley commented on gene: RBFOX2
Congenital Heart Defect v0.413 KDR Ain Roesley Classified gene: KDR as Green List (high evidence)
Congenital Heart Defect v0.413 KDR Ain Roesley Gene: kdr has been classified as Green List (High Evidence).
Congenital Heart Defect v0.413 KDR Ain Roesley Classified gene: KDR as Green List (high evidence)
Congenital Heart Defect v0.413 KDR Ain Roesley Gene: kdr has been classified as Green List (High Evidence).
Congenital Heart Defect v0.413 KDR Ain Roesley Classified gene: KDR as Green List (high evidence)
Congenital Heart Defect v0.413 KDR Ain Roesley Gene: kdr has been classified as Green List (High Evidence).
Congenital Heart Defect v0.412 KDR Ain Roesley reviewed gene: KDR: Rating: GREEN; Mode of pathogenicity: None; Publications: 34113005, 30232381, 28991257, 30232381; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes
Congenital Heart Defect v0.412 DLG5 Zornitza Stark Marked gene: DLG5 as ready
Congenital Heart Defect v0.412 DLG5 Zornitza Stark Gene: dlg5 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.412 DLG5 Zornitza Stark Classified gene: DLG5 as Green List (high evidence)
Congenital Heart Defect v0.412 DLG5 Zornitza Stark Gene: dlg5 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.411 DLG5 Zornitza Stark gene: DLG5 was added
gene: DLG5 was added to Congenital Heart Defect. Sources: Expert list
Mode of inheritance for gene: DLG5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DLG5 were set to 32631816
Phenotypes for gene: DLG5 were set to Yuksel-Vogel-Bauer syndrome, MIM#620703
Review for gene: DLG5 was set to GREEN
Added comment: Four unrelated families reported, supportive Xenopus animal model data. Cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations.
Sources: Expert list
Congenital Heart Defect v0.410 MYOCD Zornitza Stark Classified gene: MYOCD as Amber List (moderate evidence)
Congenital Heart Defect v0.410 MYOCD Zornitza Stark Gene: myocd has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.409 MYOCD Zornitza Stark edited their review of gene: MYOCD: Added comment: Single family with bi-allelic disease reported, which seems to be more severe expression of the mono-allelic disease, hence the Amber (rather than Red) rating.; Changed rating: AMBER
Congenital Heart Defect v0.409 GATA4 Zornitza Stark Marked gene: GATA4 as ready
Congenital Heart Defect v0.409 GATA4 Zornitza Stark Gene: gata4 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.409 GATA4 Zornitza Stark Phenotypes for gene: GATA4 were changed from to Atrial septal defect 2 MIM#607941; Atrioventricular septal defect 4 MIM#614430; Ventricular septal defect 1 MIM#614429
Congenital Heart Defect v0.408 GATA4 Zornitza Stark Publications for gene: GATA4 were set to
Congenital Heart Defect v0.407 GATA4 Zornitza Stark Mode of inheritance for gene: GATA4 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.406 GATA4 Zornitza Stark reviewed gene: GATA4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Atrial septal defect 2 MIM#607941, Atrioventricular septal defect 4 MIM#614430, Ventricular septal defect 1 MIM#614429; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.406 GATA4 Sharyn Stockmyer reviewed gene: GATA4: Rating: GREEN; Mode of pathogenicity: None; Publications: 15810002, 12845333, 22101736, 18672102, 24000169, 29377543, 28991257; Phenotypes: Congenital heart disease - multiple types; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.406 EVC2 Zornitza Stark Marked gene: EVC2 as ready
Congenital Heart Defect v0.406 EVC2 Zornitza Stark Gene: evc2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.406 EVC2 Zornitza Stark Phenotypes for gene: EVC2 were changed from to Ellis-van Creveld syndrome (MIM#225500)
Congenital Heart Defect v0.405 EVC2 Zornitza Stark Mode of inheritance for gene: EVC2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.404 EVC2 Zornitza Stark reviewed gene: EVC2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ellis-van Creveld syndrome (MIM#225500); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.404 EVC Zornitza Stark Marked gene: EVC as ready
Congenital Heart Defect v0.404 EVC Zornitza Stark Gene: evc has been classified as Green List (High Evidence).
Congenital Heart Defect v0.404 EVC Zornitza Stark Phenotypes for gene: EVC were changed from to Ellis-van Creveld syndrome, MIM# 225500
Congenital Heart Defect v0.403 EVC Zornitza Stark Mode of inheritance for gene: EVC was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.402 EVC Zornitza Stark reviewed gene: EVC: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ellis-van Creveld syndrome, MIM# 225500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.402 ELN Zornitza Stark Marked gene: ELN as ready
Congenital Heart Defect v0.402 ELN Zornitza Stark Gene: eln has been classified as Green List (High Evidence).
Congenital Heart Defect v0.402 ELN Zornitza Stark Phenotypes for gene: ELN were changed from to Supravalvar aortic stenosis, MIM# 185500
Congenital Heart Defect v0.401 ELN Zornitza Stark Mode of inheritance for gene: ELN was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.400 ELN Zornitza Stark reviewed gene: ELN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Supravalvar aortic stenosis, MIM# 185500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.400 CREBBP Zornitza Stark Marked gene: CREBBP as ready
Congenital Heart Defect v0.400 CREBBP Zornitza Stark Gene: crebbp has been classified as Green List (High Evidence).
Congenital Heart Defect v0.400 CREBBP Zornitza Stark Phenotypes for gene: CREBBP were changed from to Rubinstein-Taybi syndrome 1 , MIM#180849
Congenital Heart Defect v0.399 CREBBP Zornitza Stark Mode of inheritance for gene: CREBBP was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.398 CREBBP Zornitza Stark reviewed gene: CREBBP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Rubinstein-Taybi syndrome 1 , MIM#180849; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.398 BMPR2 Zornitza Stark Marked gene: BMPR2 as ready
Congenital Heart Defect v0.398 BMPR2 Zornitza Stark Gene: bmpr2 has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.398 BMPR2 Zornitza Stark Phenotypes for gene: BMPR2 were changed from to Pulmonary hypertension, familial primary, 1, with or without HHT MIM#178600 Pulmonary hypertension, primary, fenfluramine or dexfenfluramine-associated MIM#178600 Pulmonary venoocclusive disease 1 MIM#265450
Congenital Heart Defect v0.397 BMPR2 Zornitza Stark Mode of inheritance for gene: BMPR2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.396 BMPR2 Zornitza Stark Classified gene: BMPR2 as Red List (low evidence)
Congenital Heart Defect v0.396 BMPR2 Zornitza Stark Gene: bmpr2 has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.395 BMPR2 Zornitza Stark reviewed gene: BMPR2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Pulmonary hypertension, familial primary, 1, with or without HHT MIM#178600 Pulmonary hypertension, primary, fenfluramine or dexfenfluramine-associated MIM#178600 Pulmonary venoocclusive disease 1 MIM#265450; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.395 B3GAT3 Zornitza Stark Marked gene: B3GAT3 as ready
Congenital Heart Defect v0.395 B3GAT3 Zornitza Stark Gene: b3gat3 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.395 B3GAT3 Zornitza Stark Phenotypes for gene: B3GAT3 were changed from to Multiple joint dislocations, short stature, craniofacial dysmorphism, with or without congenital heart defects -MIM#245600
Congenital Heart Defect v0.394 B3GAT3 Zornitza Stark Publications for gene: B3GAT3 were set to
Congenital Heart Defect v0.393 B3GAT3 Zornitza Stark Mode of inheritance for gene: B3GAT3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.392 B3GAT3 Zornitza Stark reviewed gene: B3GAT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 26754439, 31988067, 26086840, 25893793, 21763480, 24668659; Phenotypes: Multiple joint dislocations, short stature, craniofacial dysmorphism, with or without congenital heart defects -MIM#245600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.392 SMC3 Zornitza Stark Marked gene: SMC3 as ready
Congenital Heart Defect v0.392 SMC3 Zornitza Stark Gene: smc3 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.392 SMC3 Zornitza Stark Phenotypes for gene: SMC3 were changed from to Cornelia de Lange syndrome 3, MIM# 610759
Congenital Heart Defect v0.391 SMC3 Zornitza Stark Mode of inheritance for gene: SMC3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.390 SMC3 Zornitza Stark reviewed gene: SMC3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cornelia de Lange syndrome 3, MIM# 610759; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.390 SOS1 Zornitza Stark Marked gene: SOS1 as ready
Congenital Heart Defect v0.390 SOS1 Zornitza Stark Gene: sos1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.390 SOS1 Zornitza Stark Phenotypes for gene: SOS1 were changed from to Noonan syndrome 4, MIM# 610733
Congenital Heart Defect v0.389 SOS1 Zornitza Stark Mode of inheritance for gene: SOS1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.388 SOS1 Zornitza Stark reviewed gene: SOS1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Noonan syndrome 4, MIM# 610733; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.388 STRA6 Zornitza Stark Marked gene: STRA6 as ready
Congenital Heart Defect v0.388 STRA6 Zornitza Stark Gene: stra6 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.388 STRA6 Zornitza Stark Phenotypes for gene: STRA6 were changed from to Microphthalmia, syndromic 9, MIM# 601186
Congenital Heart Defect v0.387 STRA6 Zornitza Stark Mode of inheritance for gene: STRA6 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.386 STRA6 Zornitza Stark reviewed gene: STRA6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Microphthalmia, syndromic 9, MIM# 601186; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.386 TBX20 Zornitza Stark Marked gene: TBX20 as ready
Congenital Heart Defect v0.386 TBX20 Zornitza Stark Gene: tbx20 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.386 TBX20 Zornitza Stark Phenotypes for gene: TBX20 were changed from to Atrial septal defect 4, MIM# 611363
Congenital Heart Defect v0.385 TBX20 Zornitza Stark Publications for gene: TBX20 were set to
Congenital Heart Defect v0.384 TBX20 Zornitza Stark Mode of inheritance for gene: TBX20 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.383 TBX20 Zornitza Stark reviewed gene: TBX20: Rating: GREEN; Mode of pathogenicity: None; Publications: 17668378, 19762328, 33585493, 29089047; Phenotypes: Atrial septal defect 4, MIM# 611363; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.383 TBX5 Zornitza Stark Marked gene: TBX5 as ready
Congenital Heart Defect v0.383 TBX5 Zornitza Stark Gene: tbx5 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.383 TBX5 Zornitza Stark Phenotypes for gene: TBX5 were changed from to Holt-Oram syndrome, MIM# 142900
Congenital Heart Defect v0.382 TBX5 Zornitza Stark Mode of inheritance for gene: TBX5 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.381 TBX5 Zornitza Stark reviewed gene: TBX5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Holt-Oram syndrome, MIM# 142900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.381 TGFBR1 Zornitza Stark Marked gene: TGFBR1 as ready
Congenital Heart Defect v0.381 TGFBR1 Zornitza Stark Gene: tgfbr1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.381 TGFBR1 Zornitza Stark Phenotypes for gene: TGFBR1 were changed from to Loeys-Dietz syndrome 1, MIM# 609192
Congenital Heart Defect v0.380 TGFBR1 Zornitza Stark Mode of inheritance for gene: TGFBR1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.379 TGFBR1 Zornitza Stark reviewed gene: TGFBR1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Loeys-Dietz syndrome 1, MIM# 609192; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.379 TGFBR2 Zornitza Stark Marked gene: TGFBR2 as ready
Congenital Heart Defect v0.379 TGFBR2 Zornitza Stark Gene: tgfbr2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.379 TGFBR2 Zornitza Stark Phenotypes for gene: TGFBR2 were changed from to Loeys-Dietz syndrome 2, MIM# 610168
Congenital Heart Defect v0.378 TGFBR2 Zornitza Stark Mode of inheritance for gene: TGFBR2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.377 TGFBR2 Zornitza Stark reviewed gene: TGFBR2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Loeys-Dietz syndrome 2, MIM# 610168; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.377 ZIC3 Zornitza Stark Marked gene: ZIC3 as ready
Congenital Heart Defect v0.377 ZIC3 Zornitza Stark Gene: zic3 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.377 ZIC3 Zornitza Stark Phenotypes for gene: ZIC3 were changed from to Heterotaxy, visceral, 1, X-linked (MIM#306955)
Congenital Heart Defect v0.376 ZIC3 Zornitza Stark Publications for gene: ZIC3 were set to
Congenital Heart Defect v0.375 ZIC3 Zornitza Stark Mode of inheritance for gene: ZIC3 was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Congenital Heart Defect v0.374 ZIC3 Zornitza Stark reviewed gene: ZIC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 27406248, 30120289; Phenotypes: Heterotaxy, visceral, 1, X-linked (MIM#306955); Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Congenital Heart Defect v0.374 MESP1 Zornitza Stark Phenotypes for gene: MESP1 were changed from Congenital heart disease, MONDO:0005453, MESP1-related to Congenital heart disease, MONDO:0005453, MESP1-related
Congenital Heart Defect v0.374 MESP1 Zornitza Stark Phenotypes for gene: MESP1 were changed from Congenital heart disease to Congenital heart disease, MONDO:0005453, MESP1-related
Congenital Heart Defect v0.373 FOXH1 Zornitza Stark Phenotypes for gene: FOXH1 were changed from Congenital heart disease to Congenital heart disease, MONDO:0005453, FOXH1-related
Congenital Heart Defect v0.372 ACVR2B Zornitza Stark Marked gene: ACVR2B as ready
Congenital Heart Defect v0.372 ACVR2B Zornitza Stark Gene: acvr2b has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.372 NR2F2 Zornitza Stark Marked gene: NR2F2 as ready
Congenital Heart Defect v0.372 NR2F2 Zornitza Stark Gene: nr2f2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.372 NR2F2 Zornitza Stark Phenotypes for gene: NR2F2 were changed from to 46,XX sex reversal 5 - MIM#618901; Congenital heart defects, multiple types, 4 - MIM#615779
Congenital Heart Defect v0.371 NR2F2 Zornitza Stark Publications for gene: NR2F2 were set to
Congenital Heart Defect v0.370 NR2F2 Zornitza Stark Mode of inheritance for gene: NR2F2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.369 KDR Zornitza Stark Mode of inheritance for gene: KDR was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital Heart Defect v0.368 KDR Zornitza Stark Classified gene: KDR as Amber List (moderate evidence)
Congenital Heart Defect v0.368 KDR Zornitza Stark Gene: kdr has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.367 KDR Zornitza Stark edited their review of gene: KDR: Added comment: PMID 34113005: Exome sequencing in a family with two siblings affected by ToF revealed biallelic missense variants in KDR. Studies in knock-in mice and in HEK 293T cells identified embryonic lethality for one variant when occurring in the homozygous state, and a significantly reduced VEGFR2 phosphorylation for both variants.

Rare variant burden analysis conducted in a set of 1,569 patients of European descent with ToF identified a 46-fold enrichment of protein-truncating variants (PTVs) in TOF cases compared to controls (P = 7 × 10-11).

At this stage MOI unclear and insufficient evidence for either MOI.; Changed rating: AMBER; Changed publications: 34113005; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital Heart Defect v0.367 KMT2B Violeta Velkoska-Ivanova changed review comment from: There is insufficient evidence in the published data to rate this gene as green in the context of congenital heart disease. The supporting evidence for rating this gene AMBER is as follows:
No heart abnormalities were noted in the two KMT2B-associated disease phenotypes listed in OMIM ( both reviewed in 2022).
The GenCC database( https://thegencc.org/) has summarised evidence from four reputable submitters: Genomic England Panel App, ClinGen, Ambry Genetics and Orphanet). Three classifications (two supportive, one strong) implicate KMT2B in two diseases: Dystonia,28, childhood-onset (MONDO:0015004; OMIM: 617284) and Complex Neurodevelopmental Disorder with Motor features (MONDO: 0100516) where the KMT2B variations are inherited in autosomal dominant mode.
The ClinGen evaluation (The Clinical Genome Resource), with ten variants (missense, nonsense, and frameshift) being reported in 10 probands in 2 publications (PMIDs: 29276005, 33150406) and also in a non-human animal model (PMID: 23426673) provides definitive evidence for the KMT2B gene relationship with autosomal dominant, Complex Neurodevelopmental Disorder with Motor features (MONDO: 0100516). Regarding dosage sensitivity, there is sufficient evidence that this gene exhibits haploinsufficiency and is intolerant to LoF variation.
The G2P database (https://www.ebi.ac.uk/gene2phenotype/) lists the KMT2B-associated complex early-onset dystonia in the Developmental Delay panel. Also, the KMT2B is absent from the Cardiac G2P, a publicly available resource designed for filtering and analysing genetic variants of inherited cardiac conditions (ICC)(PMID 37872640).
The largest cohort with KMT2B variants (133 patients: 53 as the initial study cohort in addition to 80 published cases)(PMID:33150406) provides a detailed delineation of their clinical phenotype and molecular genetic features. Although this study emphasised that patients with chromosomal deletions and protein-truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants, it reported on new disease features ( i.e. atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype). It also identified co-morbidities ( i.e. risk of status dystonicus, intrauterine growth retardation, and endocrinopathies); however, it failed to associate the KMT2B gene with congenital abnormalities of the heart.
; to: There is insufficient evidence in the published data to rate this gene as green in the context of congenital heart disease. The supporting evidence for rating this gene AMBER is as follows:
No heart abnormalities were noted in the two KMT2B-associated disease phenotypes listed in OMIM ( both reviewed in 2022).
The GenCC database( https://thegencc.org/) has summarised evidence from four reputable submitters: Genomic England Panel App, ClinGen, Ambry Genetics and Orphanet). Three classifications (two supportive, one strong) implicate KMT2B in two diseases: Dystonia,28, childhood-onset (MONDO:0015004; OMIM: 617284) and Complex Neurodevelopmental Disorder with Motor features (MONDO: 0100516) where the KMT2B variations are inherited in autosomal dominant mode.
The ClinGen evaluation (The Clinical Genome Resource), with ten variants (missense, nonsense, and frameshift) being reported in 10 probands in 2 publications (PMIDs: 29276005, 33150406) and also in a non-human animal model (PMID: 23426673) provides definitive evidence for the KMT2B gene relationship with autosomal dominant, Complex Neurodevelopmental Disorder with Motor features (MONDO: 0100516). Regarding dosage sensitivity, there is sufficient evidence that this gene exhibits haploinsufficiency and is intolerant to LoF variation.
The G2P database (https://www.ebi.ac.uk/gene2phenotype/) lists the KMT2B-associated complex early-onset dystonia in the Developmental Delay panel whose scope is" severe undiagnosed neurodevelopmental disorder and/or congenital anomalies, abnormal growth parameters, dysmorphic features and unusual behavioural phenotypes" and as such is part of the DD2P panel in Panel App England. Also, the KMT2B is absent from the Cardiac G2P, a publicly available resource designed for filtering and analysing genetic variants of inherited cardiac conditions (ICC)(PMID 37872640).
The largest cohort of 133 patients with KMT2B variants (PMID:33150406) delineates their clinical phenotype and molecular genetic features. Although this study emphasised that patients with chromosomal deletions and protein-truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants, it reported on new disease features ( i.e. atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype). It also identified co-morbidities ( i.e. risk of status dystonicus, intrauterine growth retardation, and endocrinopathies); however, it failed to associate the KMT2B gene with congenital abnormalities of the heart.
However, the following evidence may be considered when upgrading the KMT2B gene to Green:
KMT2B methyltransferase is a family of histone-modifying enzymes (KMTs) that catalyse the methylation of lysine 4 of the Histone 3 protein and regulate transcriptional activity at the chromatin level. As methylation is critical in transcriptional changes occurring during development, it is not unexpected that deregulated methylation marks are found in developmental disorders, human aging, and cancer. A range of neurodevelopmental disorders is caused by pathogenic variants in genes regulating chromatin function and structure that display abnormal DNA methylation patterns (episignatures) in peripheral blood. Similarly, deregulation of histone lysine methylation, essential during cardiac development, is associated with cardiac disease. ( 35506254)
A recent review states that the known KMT2B paralogs (Gene Cards), KMT2A, KMT2C and KMT2D exhibit regulatory roles during heart development or disease (as defined by supporting data from multiple model systems and /or by disease association. (37504561).
One such example is the KMT2D gene that confusingly shares the same alternate name as KMT2B- MLL2 despite the different genomic locations of both genes and other differences. Molecular rearrangements of KMT2D are associated with Kabuki Syndrome 1(KS) (OMIM: 147920) where, in addition to neurodevelopmental presentation, congenital heart defect, ventricular and atrial septal defect are also part of the phenotypic spectrum.
Comparison of the methylation patterns in peripheral blood from patients with KMT2-dystonia, KMT2-Kabuki Syndrome and controls showed that most DNA regions with altered methylation patterns differ between these two disorders and controls with KMT2B being hypermethylated. The KMT2B is unique among ’chromatin neurodevelopmental disorders’ genes as its most prominent clinical feature is childhood-onset dystonia rather than developmental delay or congenital anomalies. (PMID:35506254).
The KMT2B paralogs, KMT2A and KMT2D supported by patient phenotypic presentation and likely valid functional evidence in animal models have been investigated thus far as candidate genes in genomic sequencing studies of cardiac disease, including those for patients with congenital heart defect (PMID3378394;25972376;28884922). Thus far, the function of KMT2B in the context of congenital heart disease is yet to be phenotypically confirmed and recapitulated through further research.
Congenital Heart Defect v0.367 SMG9 Zornitza Stark Marked gene: SMG9 as ready
Congenital Heart Defect v0.367 SMG9 Zornitza Stark Gene: smg9 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.367 SMG9 Zornitza Stark Phenotypes for gene: SMG9 were changed from to Heart and brain malformation syndrome, MIM# 616920
Congenital Heart Defect v0.366 SMG9 Zornitza Stark Publications for gene: SMG9 were set to 27018474
Congenital Heart Defect v0.365 SMG9 Zornitza Stark Mode of inheritance for gene: SMG9 was changed from Other to BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.364 SMG9 Zornitza Stark Classified gene: SMG9 as Green List (high evidence)
Congenital Heart Defect v0.364 SMG9 Zornitza Stark Gene: smg9 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.363 SMG9 Zornitza Stark reviewed gene: SMG9: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Heart and brain malformation syndrome, MIM# 616920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.363 TXNL4A Zornitza Stark Marked gene: TXNL4A as ready
Congenital Heart Defect v0.363 TXNL4A Zornitza Stark Gene: txnl4a has been classified as Green List (High Evidence).
Congenital Heart Defect v0.363 TXNL4A Zornitza Stark Classified gene: TXNL4A as Green List (high evidence)
Congenital Heart Defect v0.363 TXNL4A Zornitza Stark Gene: txnl4a has been classified as Green List (High Evidence).
Congenital Heart Defect v0.362 TXNL4A Zornitza Stark Tag SV/CNV tag was added to gene: TXNL4A.
Tag UTR tag was added to gene: TXNL4A.
Congenital Heart Defect v0.362 TXNL4A Zornitza Stark reviewed gene: TXNL4A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Burn-McKeown syndrome - MIM#608572; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.362 WASHC5 Zornitza Stark Marked gene: WASHC5 as ready
Congenital Heart Defect v0.362 WASHC5 Zornitza Stark Gene: washc5 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.362 WASHC5 Zornitza Stark Classified gene: WASHC5 as Green List (high evidence)
Congenital Heart Defect v0.362 WASHC5 Zornitza Stark Gene: washc5 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.361 WASHC5 Zornitza Stark reviewed gene: WASHC5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ritscher-Schinzel syndrome 1, MIM# 220210; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.361 PIGL Zornitza Stark Marked gene: PIGL as ready
Congenital Heart Defect v0.361 PIGL Zornitza Stark Gene: pigl has been classified as Green List (High Evidence).
Congenital Heart Defect v0.361 PIGL Zornitza Stark Classified gene: PIGL as Green List (high evidence)
Congenital Heart Defect v0.361 PIGL Zornitza Stark Gene: pigl has been classified as Green List (High Evidence).
Congenital Heart Defect v0.360 PIGL Zornitza Stark Publications for gene: PIGL were set to
Congenital Heart Defect v0.359 PIGL Zornitza Stark Phenotypes for gene: PIGL were changed from to CHIME syndrome, MIIM# 280000
Congenital Heart Defect v0.358 PIGV Zornitza Stark Marked gene: PIGV as ready
Congenital Heart Defect v0.358 PIGV Zornitza Stark Gene: pigv has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.358 PIGV Zornitza Stark Phenotypes for gene: PIGV were changed from mental retardation; seizures and hypotonia; hyperphosphatasia; facial dysmorphism; variable degrees of brachytelephalangy to Hyperphosphatasia with impaired intellectual development syndrome 1, MIM# 239300
Congenital Heart Defect v0.357 PIGV Zornitza Stark Classified gene: PIGV as Amber List (moderate evidence)
Congenital Heart Defect v0.357 PIGV Zornitza Stark Gene: pigv has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.356 PIGV Zornitza Stark reviewed gene: PIGV: Rating: AMBER; Mode of pathogenicity: None; Publications: 24129430; Phenotypes: Hyperphosphatasia with impaired intellectual development syndrome 1, MIM# 239300; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.356 CRELD1 Zornitza Stark Marked gene: CRELD1 as ready
Congenital Heart Defect v0.356 CRELD1 Zornitza Stark Gene: creld1 has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.356 CRELD1 Zornitza Stark Phenotypes for gene: CRELD1 were changed from to Atrioventricular septal defect, susceptibility to, 2; Atrioventricular septal defect, partial, with heterotaxy syndrome MIM#606217
Congenital Heart Defect v0.355 CRELD1 Zornitza Stark Publications for gene: CRELD1 were set to
Congenital Heart Defect v0.354 CRELD1 Zornitza Stark Mode of inheritance for gene: CRELD1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.353 CRELD1 Zornitza Stark Classified gene: CRELD1 as Red List (low evidence)
Congenital Heart Defect v0.353 CRELD1 Zornitza Stark Gene: creld1 has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.352 CRELD1 Zornitza Stark reviewed gene: CRELD1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Atrioventricular septal defect, susceptibility to, 2, Atrioventricular septal defect, partial, with heterotaxy syndrome MIM#606217; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.352 ARID1A Zornitza Stark Marked gene: ARID1A as ready
Congenital Heart Defect v0.352 ARID1A Zornitza Stark Gene: arid1a has been classified as Green List (High Evidence).
Congenital Heart Defect v0.352 ARID1A Zornitza Stark Phenotypes for gene: ARID1A were changed from to Coffin-Siris syndrome MONDO:0015452
Congenital Heart Defect v0.351 ARID1A Zornitza Stark Publications for gene: ARID1A were set to
Congenital Heart Defect v0.350 ARID1A Zornitza Stark Mode of inheritance for gene: ARID1A was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.349 MAP3K7 Zornitza Stark Marked gene: MAP3K7 as ready
Congenital Heart Defect v0.349 MAP3K7 Zornitza Stark Gene: map3k7 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.349 MAP3K7 Zornitza Stark Classified gene: MAP3K7 as Green List (high evidence)
Congenital Heart Defect v0.349 MAP3K7 Zornitza Stark Gene: map3k7 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.348 NUP188 Zornitza Stark Marked gene: NUP188 as ready
Congenital Heart Defect v0.348 NUP188 Zornitza Stark Gene: nup188 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.348 NUP188 Zornitza Stark Classified gene: NUP188 as Green List (high evidence)
Congenital Heart Defect v0.348 NUP188 Zornitza Stark Gene: nup188 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.347 JAG1 Zornitza Stark Marked gene: JAG1 as ready
Congenital Heart Defect v0.347 JAG1 Zornitza Stark Gene: jag1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.347 JAG1 Zornitza Stark Phenotypes for gene: JAG1 were changed from to Alagille syndrome 1 #118450
Congenital Heart Defect v0.346 JAG1 Zornitza Stark Publications for gene: JAG1 were set to
Congenital Heart Defect v0.345 JAG1 Zornitza Stark Mode of inheritance for gene: JAG1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.344 GATA6 Zornitza Stark Marked gene: GATA6 as ready
Congenital Heart Defect v0.344 GATA6 Zornitza Stark Gene: gata6 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.344 GATA6 Zornitza Stark Mode of inheritance for gene: GATA6 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.343 GATA6 Zornitza Stark Publications for gene: GATA6 were set to 22158542; 23223019; 23635550
Congenital Heart Defect v0.342 GATA6 Zornitza Stark Phenotypes for gene: GATA6 were changed from to Pancreatic agenesis and congenital heart defects, MIM# 600001
Congenital Heart Defect v0.341 GATA6 Zornitza Stark Publications for gene: GATA6 were set to
Congenital Heart Defect v0.340 GATA6 Zornitza Stark Mode of inheritance for gene: GATA6 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.339 BRAF Zornitza Stark Marked gene: BRAF as ready
Congenital Heart Defect v0.339 BRAF Zornitza Stark Gene: braf has been classified as Green List (High Evidence).
Congenital Heart Defect v0.339 BRAF Zornitza Stark Phenotypes for gene: BRAF were changed from to Cardiofaciocutaneous syndrome, 115150; Noonan syndrome 7, 613706
Congenital Heart Defect v0.338 BRAF Zornitza Stark Publications for gene: BRAF were set to
Congenital Heart Defect v0.337 BRAF Zornitza Stark Mode of pathogenicity for gene: BRAF was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Congenital Heart Defect v0.336 BRAF Zornitza Stark Mode of inheritance for gene: BRAF was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.335 MED12 Zornitza Stark Marked gene: MED12 as ready
Congenital Heart Defect v0.335 MED12 Zornitza Stark Gene: med12 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.335 MED12 Zornitza Stark Phenotypes for gene: MED12 were changed from Dilated cardiomyopathy (DCM); left ventricular non-compaction (LVNC); dilated cardiomyopathy (DCM); arrhythmia; ventricular septal defect (VSD) to Hardikar syndrome, MIM# 301068; Lujan-Fryns syndrome, MIM# 309520; Ohdo syndrome, X-linked, MIM# 300895
Congenital Heart Defect v0.334 MED12 Zornitza Stark Classified gene: MED12 as Green List (high evidence)
Congenital Heart Defect v0.334 MED12 Zornitza Stark Gene: med12 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.333 MED12 Zornitza Stark reviewed gene: MED12: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hardikar syndrome, MIM# 301068, Lujan-Fryns syndrome, MIM# 309520, Ohdo syndrome, X-linked, MIM# 300895; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Congenital Heart Defect v0.333 THOC6 Zornitza Stark Marked gene: THOC6 as ready
Congenital Heart Defect v0.333 THOC6 Zornitza Stark Gene: thoc6 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.333 THOC6 Zornitza Stark Phenotypes for gene: THOC6 were changed from VSD/ASD; severe aortic and left ventricular hypoplasia; Mild dilation of the right chambers and a mild myocardial hypertrophy secondary to a chronic hypertension; ventriculomegaly to Beaulieu-Boycott-Innes syndrome (OMIM#613680)
Congenital Heart Defect v0.332 THOC6 Zornitza Stark Classified gene: THOC6 as Green List (high evidence)
Congenital Heart Defect v0.332 THOC6 Zornitza Stark Gene: thoc6 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.331 THOC6 Zornitza Stark reviewed gene: THOC6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Beaulieu-Boycott-Innes syndrome (OMIM#613680); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.331 LTBP2 Zornitza Stark Marked gene: LTBP2 as ready
Congenital Heart Defect v0.331 LTBP2 Zornitza Stark Gene: ltbp2 has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.331 LTBP2 Zornitza Stark Publications for gene: LTBP2 were set to 33098376; 35245370; 31512380; 22539340
Congenital Heart Defect v0.330 LTBP2 Zornitza Stark Mode of inheritance for gene: LTBP2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital Heart Defect v0.329 LTBP2 Zornitza Stark Classified gene: LTBP2 as Red List (low evidence)
Congenital Heart Defect v0.329 LTBP2 Zornitza Stark Gene: ltbp2 has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.328 LTBP2 Zornitza Stark reviewed gene: LTBP2: Rating: RED; Mode of pathogenicity: None; Publications: 30565850; Phenotypes: Marfan-like disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.328 MYBPC3 Zornitza Stark Marked gene: MYBPC3 as ready
Congenital Heart Defect v0.328 MYBPC3 Zornitza Stark Gene: mybpc3 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.328 MYBPC3 Zornitza Stark Publications for gene: MYBPC3 were set to 25335496; 16679492
Congenital Heart Defect v0.327 MYBPC3 Zornitza Stark Phenotypes for gene: MYBPC3 were changed from to Cardiomyopathy, hypertrophic, 4, MIM# 115197
Congenital Heart Defect v0.327 MYBPC3 Zornitza Stark Publications for gene: MYBPC3 were set to
Congenital Heart Defect v0.326 MYBPC3 Zornitza Stark Mode of inheritance for gene: MYBPC3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.325 MYBPC3 Zornitza Stark Classified gene: MYBPC3 as Amber List (moderate evidence)
Congenital Heart Defect v0.325 MYBPC3 Zornitza Stark Gene: mybpc3 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.324 MYBPC3 Zornitza Stark reviewed gene: MYBPC3: Rating: AMBER; Mode of pathogenicity: None; Publications: 25335496, 16679492; Phenotypes: Cardiomyopathy, hypertrophic, 4, MIM# 115197; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.324 PKD1L1 Zornitza Stark Marked gene: PKD1L1 as ready
Congenital Heart Defect v0.324 PKD1L1 Zornitza Stark Gene: pkd1l1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.324 PKD1L1 Zornitza Stark Classified gene: PKD1L1 as Green List (high evidence)
Congenital Heart Defect v0.324 PKD1L1 Zornitza Stark Gene: pkd1l1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.323 ARID1B Zornitza Stark Marked gene: ARID1B as ready
Congenital Heart Defect v0.323 ARID1B Zornitza Stark Gene: arid1b has been classified as Green List (High Evidence).
Congenital Heart Defect v0.323 ARID1B Zornitza Stark Publications for gene: ARID1B were set to 35579625; 35445787; 29549119; 34324492
Congenital Heart Defect v0.322 ARID1B Zornitza Stark Phenotypes for gene: ARID1B were changed from to Coffin-Siris syndrome 1, MIM# 135900
Congenital Heart Defect v0.321 ARID1B Zornitza Stark Publications for gene: ARID1B were set to
Congenital Heart Defect v0.320 ARID1B Zornitza Stark Mode of inheritance for gene: ARID1B was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.319 KMT2B Zornitza Stark Marked gene: KMT2B as ready
Congenital Heart Defect v0.319 KMT2B Zornitza Stark Gene: kmt2b has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.319 KMT2B Zornitza Stark Phenotypes for gene: KMT2B were changed from to Dystonia 28,Childhood-onset; DYT28(617284); Intellectual Developmental disorder, Autosomal dominant; MRD68(619934)
Congenital Heart Defect v0.318 KMT2B Zornitza Stark Publications for gene: KMT2B were set to
Congenital Heart Defect v0.317 KMT2B Zornitza Stark Mode of inheritance for gene: KMT2B was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.316 KMT2B Zornitza Stark Classified gene: KMT2B as Red List (low evidence)
Congenital Heart Defect v0.316 KMT2B Zornitza Stark Gene: kmt2b has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.315 KMT2B Zornitza Stark reviewed gene: KMT2B: Rating: RED; Mode of pathogenicity: None; Publications: 33150406; Phenotypes: Dystonia 28,Childhood-onset, DYT28(617284), Intellectual Developmental disorder, Autosomal dominant, MRD68(619934); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.315 KMT2B Violeta Velkoska-Ivanova changed review comment from: There is insufficient evidence in the published data to rate this gene as green in the context of congenital heart disease. The supporting evidence for rating this gene AMBER is as follows:
No heart abnormalities were noted in the synopsis of the two KMT2B-associated disease phenotypes listed in OMIM ( both reviewed in 2022).
The GenCC database( https://thegencc.org/) has summarised evidence from four reputable submitters: Genomic England Panel App, ClinGen, Ambry Genetics and Orphanet). Three classifications (two supportive, one strong) implicate KMT2B in two diseases: Dystonia,28, childhood-onset (MONDO:0015004; OMIM: 617284) and Complex Neurodevelopmental Disorder with Motor features (MONDO: 0100516) where the KMT2B variations are inherited in autosomal dominant mode.
The ClinGen evaluation (The Clinical Genome Resource), with ten variants (missense, nonsense, and frameshift) being reported in 10 probands in 2 publications (PMIDs: 29276005, 33150406) and also in a non-human animal model (PMID: 23426673) provides definitive evidence for the KMT2B gene relationship with autosomal dominant, Complex Neurodevelopmental Disorder with Motor features (MONDO: 0100516). Regarding dosage sensitivity, there is sufficient evidence that this gene exhibits haploinsufficiency and is intolerant to LoF variation.
The G2P database (https://www.ebi.ac.uk/gene2phenotype/) lists the KMT2B-associated complex early-onset dystonia in the Developmental Delay panel. Also, the KMT2B is absent from the Cardiac G2P, a publicly available resource designed for filtering and analysing genetic variants of inherited cardiac conditions (ICC)(PMID 37872640).
The largest cohort with KMT2B variants (133 patients: 53 as the initial study cohort in addition to 80 published cases)(PMID:33150406) provides a detailed delineation of their clinical phenotype and molecular genetic features. Although this study emphasised that patients with chromosomal deletions and protein-truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants, it reported on new disease features ( i.e. atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype). It also identified co-morbidities ( i.e. risk of status dystonicus, intrauterine growth retardation, and endocrinopathies); however, it failed to associate the KMT2B gene with congenital abnormalities of the heart.; to: There is insufficient evidence in the published data to rate this gene as green in the context of congenital heart disease. The supporting evidence for rating this gene AMBER is as follows:
No heart abnormalities were noted in the two KMT2B-associated disease phenotypes listed in OMIM ( both reviewed in 2022).
The GenCC database( https://thegencc.org/) has summarised evidence from four reputable submitters: Genomic England Panel App, ClinGen, Ambry Genetics and Orphanet). Three classifications (two supportive, one strong) implicate KMT2B in two diseases: Dystonia,28, childhood-onset (MONDO:0015004; OMIM: 617284) and Complex Neurodevelopmental Disorder with Motor features (MONDO: 0100516) where the KMT2B variations are inherited in autosomal dominant mode.
The ClinGen evaluation (The Clinical Genome Resource), with ten variants (missense, nonsense, and frameshift) being reported in 10 probands in 2 publications (PMIDs: 29276005, 33150406) and also in a non-human animal model (PMID: 23426673) provides definitive evidence for the KMT2B gene relationship with autosomal dominant, Complex Neurodevelopmental Disorder with Motor features (MONDO: 0100516). Regarding dosage sensitivity, there is sufficient evidence that this gene exhibits haploinsufficiency and is intolerant to LoF variation.
The G2P database (https://www.ebi.ac.uk/gene2phenotype/) lists the KMT2B-associated complex early-onset dystonia in the Developmental Delay panel. Also, the KMT2B is absent from the Cardiac G2P, a publicly available resource designed for filtering and analysing genetic variants of inherited cardiac conditions (ICC)(PMID 37872640).
The largest cohort with KMT2B variants (133 patients: 53 as the initial study cohort in addition to 80 published cases)(PMID:33150406) provides a detailed delineation of their clinical phenotype and molecular genetic features. Although this study emphasised that patients with chromosomal deletions and protein-truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants, it reported on new disease features ( i.e. atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype). It also identified co-morbidities ( i.e. risk of status dystonicus, intrauterine growth retardation, and endocrinopathies); however, it failed to associate the KMT2B gene with congenital abnormalities of the heart.
Congenital Heart Defect v0.315 KMT2B Violeta Velkoska-Ivanova changed review comment from: There is insufficient evidence in the published data to rate this gene as green in the context of congenital heart disease. The supporting evidence for rating this gene AMBER is as follows:
No heart abnormalities were noted in the synopsis of the two KMT2B-associated disease phenotypes listed in OMIM ( both reviewed in 2022).
The GenCC database( https://thegencc.org/) has summarised evidence from four reputable submitters: Genomic England Panel App, ClinGen, Ambry Genetics and Orphanet). Three classifications (two supportive, one strong) implicate KMT2B in two diseases: Dystonia,28, childhood-onset (MONDO:0015004; OMIM: 617284) and Complex Neurodevelopmental Disorder with Motor features (MONDO: 0100516) where the KMT2B variations are inherited in autosomal dominant mode.
The ClinGen evaluation (The Clinical Genome Resource), with ten variants (missense, nonsense, and frameshift) being reported in 10 probands in 2 publications (PMIDs: 29276005, 33150406) and also in a non-human animal model (PMID: 23426673) provides definitive evidence for the KMT2B gene relationship with autosomal dominant, Complex Neurodevelopmental Disorder with Motor features (MONDO: 0100516). Regarding dosage sensitivity, there is sufficient evidence that this gene exhibits haploinsufficiency and is intolerant to LoF variation.
The G2P database (https://www.ebi.ac.uk/gene2phenotype/) only enlists the KMT2B gene in the Developmental Delay panel. The KMT2B is absent from the Cardiac G2P, a publicly available resource designed to aid in the filtering and analysing genetic variants of inherited cardiac conditions (ICC)(PMID 37872640).
The largest cohort with KMT2B variants (133 patients: 53 as the initial study cohort in addition to 80 published cases)(PMID:33150406) provides a detailed delineation of their clinical phenotype and molecular genetic features. Although this study emphasised that patients with chromosomal deletions and protein-truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants, it reported on new disease features ( i.e. atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype). It also identified co-morbidities ( i.e. risk of status dystonicus, intrauterine growth retardation, and endocrinopathies); however, it failed to associate the KMT2B gene with congenital abnormalities of the heart.; to: There is insufficient evidence in the published data to rate this gene as green in the context of congenital heart disease. The supporting evidence for rating this gene AMBER is as follows:
No heart abnormalities were noted in the synopsis of the two KMT2B-associated disease phenotypes listed in OMIM ( both reviewed in 2022).
The GenCC database( https://thegencc.org/) has summarised evidence from four reputable submitters: Genomic England Panel App, ClinGen, Ambry Genetics and Orphanet). Three classifications (two supportive, one strong) implicate KMT2B in two diseases: Dystonia,28, childhood-onset (MONDO:0015004; OMIM: 617284) and Complex Neurodevelopmental Disorder with Motor features (MONDO: 0100516) where the KMT2B variations are inherited in autosomal dominant mode.
The ClinGen evaluation (The Clinical Genome Resource), with ten variants (missense, nonsense, and frameshift) being reported in 10 probands in 2 publications (PMIDs: 29276005, 33150406) and also in a non-human animal model (PMID: 23426673) provides definitive evidence for the KMT2B gene relationship with autosomal dominant, Complex Neurodevelopmental Disorder with Motor features (MONDO: 0100516). Regarding dosage sensitivity, there is sufficient evidence that this gene exhibits haploinsufficiency and is intolerant to LoF variation.
The G2P database (https://www.ebi.ac.uk/gene2phenotype/) lists the KMT2B-associated complex early-onset dystonia in the Developmental Delay panel. Also, the KMT2B is absent from the Cardiac G2P, a publicly available resource designed for filtering and analysing genetic variants of inherited cardiac conditions (ICC)(PMID 37872640).
The largest cohort with KMT2B variants (133 patients: 53 as the initial study cohort in addition to 80 published cases)(PMID:33150406) provides a detailed delineation of their clinical phenotype and molecular genetic features. Although this study emphasised that patients with chromosomal deletions and protein-truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants, it reported on new disease features ( i.e. atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype). It also identified co-morbidities ( i.e. risk of status dystonicus, intrauterine growth retardation, and endocrinopathies); however, it failed to associate the KMT2B gene with congenital abnormalities of the heart.
Congenital Heart Defect v0.315 KMT2B Violeta Velkoska-Ivanova changed review comment from: There is insufficient evidence in the published data to rate this gene as green in the context of congenital heart disease.
The Gene Cards summary emphasises the
The supporting evidence for rating this gene AMBER is as follows:
No heart abnormalities have been noted in the synopsis of two phenotypes listed in OMIM ( both reviewed in the year 2022).
The GenCC database( https://thegencc.org/) has summarised evidence from four reputable submitters: Genomic England Panel App, ClinGen, Ambry Genetics and Orphanet). Three classifications (two supportive, one strong) implicate KMT2B in two diseases: Dystonia,28, childhood-onset (MONDO:0015004; OMIM: 617284) and Complex Neurodevelopmental Disorder with Motor features (MONDO: 0100516) where the KMT2B variations are inherited in autosomal dominant mode.
The KMT2B gene has been evaluated in ClinGen (The Clinical Genome Resource), with ten variants (missense, nonsense, and frameshift) being reported in 10 probands in 2 publications (PMIDs: 29276005, 33150406) and also in a non-human animal model (PMID: 23426673) providing definitive evidence for the KMT2B gene relationship with autosomal dominant, Complex Neurodevelopmental Disorder with Motor features (MONDO: 0100516).In terms of dosage sensitivity, there is sufficient evidence this gene exhibits haploinsufficiency and is intolerant to LoF variation.
The G2P database (https://www.ebi.ac.uk/gene2phenotype/) only enlists the KMT2B gene in the Developmental Delay panel. The KMT2B is absent from the Cardiac G2P, a publicly available resource designed to aid in the filtering and analysing genetic variants of inherited cardiac conditions (ICC)(PMID 37872640).
The largest cohort with KMT2B variants (133 patients: 53 as the initial study cohort in addition to 80 published cases)(PMID:33150406) provides a detailed delineation of their clinical phenotype and molecular genetic features. Although this study emphasised that patients with chromosomal deletions and protein-truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants, it reported on new disease features ( i.e. atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype). It also identified co-morbidities ( i.e. risk of status dystonicus, intrauterine growth retardation, and endocrinopathies); however, it failed to associate the KMT2B gene with congenital abnormalities of the heart.; to: There is insufficient evidence in the published data to rate this gene as green in the context of congenital heart disease. The supporting evidence for rating this gene AMBER is as follows:
No heart abnormalities were noted in the synopsis of the two KMT2B-associated disease phenotypes listed in OMIM ( both reviewed in 2022).
The GenCC database( https://thegencc.org/) has summarised evidence from four reputable submitters: Genomic England Panel App, ClinGen, Ambry Genetics and Orphanet). Three classifications (two supportive, one strong) implicate KMT2B in two diseases: Dystonia,28, childhood-onset (MONDO:0015004; OMIM: 617284) and Complex Neurodevelopmental Disorder with Motor features (MONDO: 0100516) where the KMT2B variations are inherited in autosomal dominant mode.
The ClinGen evaluation (The Clinical Genome Resource), with ten variants (missense, nonsense, and frameshift) being reported in 10 probands in 2 publications (PMIDs: 29276005, 33150406) and also in a non-human animal model (PMID: 23426673) provides definitive evidence for the KMT2B gene relationship with autosomal dominant, Complex Neurodevelopmental Disorder with Motor features (MONDO: 0100516). Regarding dosage sensitivity, there is sufficient evidence that this gene exhibits haploinsufficiency and is intolerant to LoF variation.
The G2P database (https://www.ebi.ac.uk/gene2phenotype/) only enlists the KMT2B gene in the Developmental Delay panel. The KMT2B is absent from the Cardiac G2P, a publicly available resource designed to aid in the filtering and analysing genetic variants of inherited cardiac conditions (ICC)(PMID 37872640).
The largest cohort with KMT2B variants (133 patients: 53 as the initial study cohort in addition to 80 published cases)(PMID:33150406) provides a detailed delineation of their clinical phenotype and molecular genetic features. Although this study emphasised that patients with chromosomal deletions and protein-truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants, it reported on new disease features ( i.e. atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype). It also identified co-morbidities ( i.e. risk of status dystonicus, intrauterine growth retardation, and endocrinopathies); however, it failed to associate the KMT2B gene with congenital abnormalities of the heart.
Congenital Heart Defect v0.315 KMT2B Violeta Velkoska-Ivanova edited their review of gene: KMT2B: Changed publications: PMID:29276005, 23426673, 33150406, 23665959, 37504561, 28902362, 21646717; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital Heart Defect v0.315 KMT2B Violeta Velkoska-Ivanova changed review comment from: There is insufficient evidence to rate this gene as green in the context of congenital heart disease. However, this gene is enlisted as Green in PanelApp England in the Fetal Anomalies Panel( v?????)
The supporting evidence for rating this gene AMBER is as follows:
No heart abnormalities have been noted in the synopsis of two phenotypes listed in OMIM ( both reviewed in the year 2022).
The GenCC database ( https://thegencc.org/) has summarised evidence from four reputable submitters: Genomic England Panel App, ClinGen, Ambry Genetics and Orphanet). Three classifications (two supportive, one strong) implicate KMT2B in two diseases: Dystonia,28, childhood-onset (MONDO:0015004; OMIM: 617284) and Complex Neurodevelopmental Disorder with Motor features (MONDO: 0100516) where the KMT2B variations are inherited in autosomal dominant mode.
The KMT2B gene has been evaluated in ClinGen (The Clinical Genome Resource), with ten variants (missense, nonsense, and frameshift) being reported in 10 probands in 2 publications (PMIDs: 29276005, 33150406) and also in a non-human animal model (PMID: 23426673) providing definitive evidence for the KMT2B gene relationship with autosomal dominant, Complex Neurodevelopmental Disorder with Motor features (MONDO: 0100516).In terms of dosage sensitivity, there is sufficient evidence this gene exhibits haploinsufficiency and is intolerant to LoF variation.
The G2P database (https://www.ebi.ac.uk/gene2phenotype/) only enlists the KMT2B gene in the Developmental Delay panel. The KMT2B is absent from the recently published publicly available resource, Cardiac G2P, which is designed to aid in the filtering and analysing of genetic variants of inherited cardiac conditions (ICC)(PMID 37872640).
The largest cohort with KMT2B variants (133 patients: 53 as the initial study cohort in addition to 80 published cases)(PMID:33150406) provides a detailed delineation of their clinical phenotype and molecular genetic features. Although this study emphasised that patients with chromosomal deletions and protein-truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants, it reported on new disease features ( i.e. atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype). It also identified co-morbidities ( i.e. risk of status dystonicus, intrauterine growth retardation, and endocrinopathies); however, it failed to associate the KMT2B gene with congenital abnormalities of the heart.; to: There is insufficient evidence in the published data to rate this gene as green in the context of congenital heart disease.
The Gene Cards summary emphasises the
The supporting evidence for rating this gene AMBER is as follows:
No heart abnormalities have been noted in the synopsis of two phenotypes listed in OMIM ( both reviewed in the year 2022).
The GenCC database( https://thegencc.org/) has summarised evidence from four reputable submitters: Genomic England Panel App, ClinGen, Ambry Genetics and Orphanet). Three classifications (two supportive, one strong) implicate KMT2B in two diseases: Dystonia,28, childhood-onset (MONDO:0015004; OMIM: 617284) and Complex Neurodevelopmental Disorder with Motor features (MONDO: 0100516) where the KMT2B variations are inherited in autosomal dominant mode.
The KMT2B gene has been evaluated in ClinGen (The Clinical Genome Resource), with ten variants (missense, nonsense, and frameshift) being reported in 10 probands in 2 publications (PMIDs: 29276005, 33150406) and also in a non-human animal model (PMID: 23426673) providing definitive evidence for the KMT2B gene relationship with autosomal dominant, Complex Neurodevelopmental Disorder with Motor features (MONDO: 0100516).In terms of dosage sensitivity, there is sufficient evidence this gene exhibits haploinsufficiency and is intolerant to LoF variation.
The G2P database (https://www.ebi.ac.uk/gene2phenotype/) only enlists the KMT2B gene in the Developmental Delay panel. The KMT2B is absent from the Cardiac G2P, a publicly available resource designed to aid in the filtering and analysing genetic variants of inherited cardiac conditions (ICC)(PMID 37872640).
The largest cohort with KMT2B variants (133 patients: 53 as the initial study cohort in addition to 80 published cases)(PMID:33150406) provides a detailed delineation of their clinical phenotype and molecular genetic features. Although this study emphasised that patients with chromosomal deletions and protein-truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants, it reported on new disease features ( i.e. atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype). It also identified co-morbidities ( i.e. risk of status dystonicus, intrauterine growth retardation, and endocrinopathies); however, it failed to associate the KMT2B gene with congenital abnormalities of the heart.
Congenital Heart Defect v0.315 KMT2B Violeta Velkoska-Ivanova reviewed gene: KMT2B: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID:29276005, 23426673, 33150406; Phenotypes: Dystonia 28,Childhood-onset, DYT28(617284), Intellectual Developmental disorder, Autosomal dominant, MRD68(619934); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital Heart Defect v0.315 ARID1B Michelle Wu reviewed gene: ARID1B: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: PMID: 35579625, 35445787, 29549119, 34324492; Phenotypes: Coffin-Siris syndrome 1, intellectual disability with or without nonspecific dysmorphic features; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.315 PKD1L1 Joce vd Bergen gene: PKD1L1 was added
gene: PKD1L1 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: PKD1L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PKD1L1 were set to PMID: 27616478; 31026592; 3079108; 30791085; 33655537
Phenotypes for gene: PKD1L1 were set to Heterotaxy, visceral, 8, autosomal; HTX8 (MIM617205)
Review for gene: PKD1L1 was set to GREEN
Added comment: Numerous families (6 families, 9 affected individuals) reported with heterotaxy and complex congenital heart defects, with biallelic variants (primarily nonsense, frameshift, splice site and a missense variant) in the PKD1L1 gene. Three reports with additional features (3079108, 30791085, 30791085), such as congenital asplenia, sideroblastic anemia, hydrops fetalis.

Several animal models suggest PKD1L1 plays a significant role in the development of L-R asymmetry and establish the L-R axis in vertebrate organisms, including mouse null and missense substitution models and a medaka knockout. Where complex congenital heart defects are often associated with laterality defects (ranging from situs inversus totalis (SIT) to situs

ClinVar: reports all published variants presented, plus 1 additional nonsense variant (not published). Summary: likely pathogenic/pathogenic (6 nonsense loss of function, 2 splice site and 1 missense variant), associated with autosomal visceral heterotaxy type 8, MIM 617205).
Sources: Literature
Congenital Heart Defect v0.315 MYBPC3 Yi-Wei Chao edited their review of gene: MYBPC3: Changed rating: GREEN
Congenital Heart Defect v0.315 MYBPC3 Yi-Wei Chao reviewed gene: MYBPC3: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 34097875, 25335496, 31877118, 22057632, 18467358, 36980931, 33209723; Phenotypes: Hypertrophic cardiomyopathy, bicuspid aortic valve, severe infantile cardiomyopathy, septal defect; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital Heart Defect v0.315 LTBP2 Dion Paul gene: LTBP2 was added
gene: LTBP2 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: LTBP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LTBP2 were set to 33098376; 35245370; 31512380; 22539340
Phenotypes for gene: LTBP2 were set to Atrioventricular septal defect (AVSD); Mitral valve prolapse; patent ductus arteriosus (PDA); secondary atrial septal defect; pulmonary hypertension; polydactyly
Penetrance for gene: LTBP2 were set to unknown
Mode of pathogenicity for gene: LTBP2 was set to Other
Review for gene: LTBP2 was set to RED
Added comment: OMIM (602091) LTBP2 encodes an extracellular matrix (ECM) protein that is expressed in elastic tissues and associates with fibrillin-1 (FBN1) containing microfibrils (PMID: 22539340). Due to this gene's wide association with fibrillin and elastin and corresponding ocular disorders, it is already included in the congenital glaucoma panel.

Animal model study - PMID: 31512380 LTBP2 silencing reduces myocardial oxidative stress injury, myocardial fibrosis and myocardial remodelling in rat models of dilated cardiomyopathy (DCM) by down-regulating the NF-κB signalling pathway.

PMID: 33098376 This study performed whole exome sequencing on a single 1.5-year-old female patient with complex CHD. The phenotype of this patient consisted of the following features: complete atrioventricular septal defect (AVSD), patent ductus arteriosus (PDA), secondary atrial septal defect, pulmonary hypertension, and polydactyly. WES revealed the following heterozygous variant in exon 12 of LTBP2: c.2206G>A (p.Asp736Asn), RefSeq NM_000428.2. Unfortunately, nil family data is available to power family studies. WES also identified another heterozygous variant within the TCTN3 gene. Sanger sequencing was employed to validate the variant. LTBP2 variants are associated with Weill-Marchesani syndrome 3 (WMS3, OMIM #614819), a rare connective tissue disorder characterized by short stature, brachydactyly, joint stiffness, and eye abnormalities. 39% of these patients demonstrate pulmonary and aortic stenosis (PMID: 22539340). Furthermore this study generated human pluripotent stem cell lines (with the aforementioned LTBP2 variant) which differentiated into cardiomyocytes, yielding transcriptomic analysis. Relative to the wildtype, the LTBP2 variant delayed the development of cardiomyocytes and along with the TCTN3 variant may affect contractility of cardiac myocytes and the development of the heart.

PMID: 33098376 The allele frequency of LTBP2 c.2206G>A was 0.0009, 0.0035 and 0.0008 in population databases of dbSNP, 1000Genomes, and HGVD (BGI).

PMID: 35245370 Genome-wide association study identified six candidate genes associated with mitral valve prolapse (MVP) - one of which included LTBP2. LTBP2 at 14q24.3 demonstrated high levels of protein expression with RNA-Seq confirming corresponding gene expression as a main driver. Although this study labelled LTBP2 as one of the strongest candidate genes at a particular locus for MVP, it also pinpointed a lack of sufficient concordant evidence. This study suggests TGF-B signalling as a role in isolated MVP pathogenesis - TGF-B signalling is regulated by an extracellular matrix protein encoded by LTBP2.
Sources: Literature
Congenital Heart Defect v0.315 ZFPM2 Luke Tork changed review comment from: Missense variants (and sometimes truncations) in ZFPM2 segregate in individuals with multiple types of congenital heart disease. Development of cardiac related structures involve the GATA family member genes. The ZFPM2 gene encodes the FOG2 protein, a transcriptional regulator responsible for binding to GATA, as well as the deacetylation (NuRD) complex - moderating GATA-mediated gene regulation. Hence, mutations in important residues of ZFPM2 may disrupt FOG2's interaction with GATA4 or NuRD complexes, resulting in congenital heart defects [PMID:28372585]

Phenotypes such as DIAPHRAGMATIC HERNIA 3; DIH3 [MIM:610187], TETRALOGY OF FALLOT; TOF [MIM:187500], and DOUBLE-OUTLET RIGHT VENTRICLE; DORV [MIM:217095] are commonly seen in patients with pathogenic ZFPM2 variants.; to: Missense variants (and sometimes truncations) in ZFPM2 segregate in individuals with multiple types of congenital heart disease. Development of cardiac related structures involve the GATA family member genes. The ZFPM2 gene encodes the FOG2 protein, a transcriptional regulator responsible for binding to GATA, as well as the deacetylation (NuRD) complex - moderating GATA-mediated gene regulation. Hence, mutations in important residues of ZFPM2 may disrupt FOG2's interaction with GATA4 or NuRD complexes, resulting in congenital heart defects [PMID:28372585]

Phenotypes such as DIAPHRAGMATIC HERNIA 3; DIH3 [MIM:610187], TETRALOGY OF FALLOT; TOF [MIM:187500], and DOUBLE-OUTLET RIGHT VENTRICLE; DORV [MIM:217095] are commonly seen in patients with ZFPM2 variants.
Congenital Heart Defect v0.315 ZFPM2 Luke Tork reviewed gene: ZFPM2: Rating: AMBER; Mode of pathogenicity: Other; Publications: 29018978, 25025186, 28372585, 21919901, 24702427; Phenotypes: 217095, 87500, 610187; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital Heart Defect v0.315 THOC6 Ling Sun edited their review of gene: THOC6: Changed phenotypes: Beaulieu-Boycott-Innes syndrome (OMIM#613680)
Congenital Heart Defect v0.315 THOC6 Ling Sun edited their review of gene: THOC6: Changed phenotypes: 613680
Congenital Heart Defect v0.315 THOC6 Ling Sun changed review comment from: THOC6 homozygous or compound heterozygous variants are associated with Beaulieu-Boycott-Innes syndrome (OMIM#613680). Clinical spectrum is heterogenous, with major phenotype DD and ID (Note that this gene is already on the ID panel). Some are affected with structural cardiac anomalies, therefore not all individuals with BBIS have cardiac anomalies (hence, not a major phenotype, eg. see https://databases.lovd.nl/shared/diseases/03390).

PMID 35426486: Two siblings with maternally inherited c.[298T>A;700G>T;824G>A], p.[(Trp100Arg);(Val234Leu);(Gly275Asp)] and paternally inherited c.977T>G, p.(Val326Gly) [compound het]

PMID: 30476144: A boy with mat UPD homozygous c.(298T>A; 700G>C; 824G>C)
A girl with maternally inherited c.(298T>A, 700G>C, 824G>A) and paternally inherited c.569G>A, p.(Gly190Glu) [compount het]

PMID: 32282736: A boy with paternally inherited c.664T>C (p.Trp222Arg) and maternally inherited c.945+1 G>A [compound het]
Sources: Other; to: THOC6 homozygous or compound heterozygous variants are associated with Beaulieu-Boycott-Innes syndrome (OMIM#613680). Clinical spectrum is heterogenous, with major phenotype DD and ID (Note that this gene is already on the ID panel). Some are affected with structural cardiac anomalies, therefore not all individuals with BBIS have cardiac anomalies (hence, not a major phenotype, eg. see https://databases.lovd.nl/shared/diseases/03390).

PMID 35426486: Two siblings with maternally inherited c.[298T>A;700G>T;824G>A], p.[(Trp100Arg);(Val234Leu);(Gly275Asp)] and paternally inherited c.977T>G, p.(Val326Gly) [compound het]

PMID: 30476144: A boy with mat UPD homozygous c.(298T>A; 700G>C; 824G>C)
A girl with maternally inherited c.(298T>A, 700G>C, 824G>A) and paternally inherited c.569G>A, p.(Gly190Glu) [compount het]

PMID: 32282736: A boy with paternally inherited c.664T>C (p.Trp222Arg) and maternally inherited c.945+1 G>A [compound het]

Cardiac anomalies described include VSD/ASD, severe aortic and left ventricular hypoplasia, mild dilation of the right chambers and a mild myocardial hypertrophy secondary to a chronic hypertension, ventriculomegaly

Sources: Other
Congenital Heart Defect v0.315 THOC6 Ling Sun changed review comment from: THOC6 homozygous or compound heterozygous variants are associated with Beaulieu-Boycott-Innes syndrome. Clinical spectrum is heterogenous, with major phenotype DD and ID (Note that this gene is already on the ID panel). Some are affected with structural cardiac anomalies, therefore not all individuals with BBIS have cardiac anomalies (hence, not a major phenotype, eg. see https://databases.lovd.nl/shared/diseases/03390).

PMID 35426486: Two siblings with maternally inherited c.[298T>A;700G>T;824G>A], p.[(Trp100Arg);(Val234Leu);(Gly275Asp)] and paternally inherited c.977T>G, p.(Val326Gly) [compound het]

PMID: 30476144: A boy with mat UPD homozygous c.(298T>A; 700G>C; 824G>C)
A girl with maternally inherited c.(298T>A, 700G>C, 824G>A) and paternally inherited c.569G>A, p.(Gly190Glu) [compount het]

PMID: 32282736: A boy with paternally inherited c.664T>C (p.Trp222Arg) and maternally inherited c.945+1 G>A [compound het]
Sources: Other; to: THOC6 homozygous or compound heterozygous variants are associated with Beaulieu-Boycott-Innes syndrome (OMIM#613680). Clinical spectrum is heterogenous, with major phenotype DD and ID (Note that this gene is already on the ID panel). Some are affected with structural cardiac anomalies, therefore not all individuals with BBIS have cardiac anomalies (hence, not a major phenotype, eg. see https://databases.lovd.nl/shared/diseases/03390).

PMID 35426486: Two siblings with maternally inherited c.[298T>A;700G>T;824G>A], p.[(Trp100Arg);(Val234Leu);(Gly275Asp)] and paternally inherited c.977T>G, p.(Val326Gly) [compound het]

PMID: 30476144: A boy with mat UPD homozygous c.(298T>A; 700G>C; 824G>C)
A girl with maternally inherited c.(298T>A, 700G>C, 824G>A) and paternally inherited c.569G>A, p.(Gly190Glu) [compount het]

PMID: 32282736: A boy with paternally inherited c.664T>C (p.Trp222Arg) and maternally inherited c.945+1 G>A [compound het]
Sources: Other
Congenital Heart Defect v0.315 THOC6 Ling Sun gene: THOC6 was added
gene: THOC6 was added to Congenital Heart Defect. Sources: Other
Mode of inheritance for gene: THOC6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: THOC6 were set to 35426486; 30476144; 32282736
Phenotypes for gene: THOC6 were set to VSD/ASD; severe aortic and left ventricular hypoplasia; Mild dilation of the right chambers and a mild myocardial hypertrophy secondary to a chronic hypertension; ventriculomegaly
Penetrance for gene: THOC6 were set to Incomplete
Review for gene: THOC6 was set to AMBER
Added comment: THOC6 homozygous or compound heterozygous variants are associated with Beaulieu-Boycott-Innes syndrome. Clinical spectrum is heterogenous, with major phenotype DD and ID (Note that this gene is already on the ID panel). Some are affected with structural cardiac anomalies, therefore not all individuals with BBIS have cardiac anomalies (hence, not a major phenotype, eg. see https://databases.lovd.nl/shared/diseases/03390).

PMID 35426486: Two siblings with maternally inherited c.[298T>A;700G>T;824G>A], p.[(Trp100Arg);(Val234Leu);(Gly275Asp)] and paternally inherited c.977T>G, p.(Val326Gly) [compound het]

PMID: 30476144: A boy with mat UPD homozygous c.(298T>A; 700G>C; 824G>C)
A girl with maternally inherited c.(298T>A, 700G>C, 824G>A) and paternally inherited c.569G>A, p.(Gly190Glu) [compount het]

PMID: 32282736: A boy with paternally inherited c.664T>C (p.Trp222Arg) and maternally inherited c.945+1 G>A [compound het]
Sources: Other
Congenital Heart Defect v0.315 MED12 Ling Sun gene: MED12 was added
gene: MED12 was added to Congenital Heart Defect. Sources: Other
Mode of inheritance for gene: MED12 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: MED12 were set to 32682435; 18973276; 31255603; 28724790; 20301719
Phenotypes for gene: MED12 were set to Dilated cardiomyopathy (DCM); left ventricular non-compaction (LVNC); dilated cardiomyopathy (DCM); arrhythmia; ventricular septal defect (VSD)
Penetrance for gene: MED12 were set to unknown
Mode of pathogenicity for gene: MED12 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: MED12 was set to AMBER
Added comment: MED12-associated syndromes or genetic conditions resulting from MED12 loss of function variants can encompass aortic and heart conditions within their broader diagnostic spectrum. For instance, while not universally present in all individuals with Lujan-Fryns syndrome, some may indeed exhibit heart abnormalities as an integral part of their overall clinical profile (PMID: 18973276). Additionally, congenital heart defects and aortic dilation have been sporadically reported in patients with MED12-syndromic XLID. However, these cardiac issues tend to be more consistently observed in females with Hardikar syndrome, with aortic coarctation being the most prevalent cardiac abnormality in this group (PMID: 20301719).

Moreover, research has demonstrated that mice with a cardiac-specific deletion of the Med12 gene experience disruptions in calcium cycling, disturbances in cardiac electrical activity, and ultimately develop dilated cardiomyopathy (PMID: 2872470). This suggests a critical role for MED12 in cardiac function and highlights its relevance in both research and clinical contexts.

[Submitted on behalf of Essra Bartlett 20/11/2023]
Sources: Other
Congenital Heart Defect v0.315 BRAF Penny Snell changed review comment from: Well established gene-disease association.
Cardiofaciocutaneous and Noonan syndromes present with overlapping clinical features, including congenital heart defects.

There is limited evidence for loss-of-function as a mechanism of disease for either of these phenotypes.; to: Well established gene-disease association.
Cardiofaciocutaneous and Noonan syndromes present with overlapping clinical features, including congenital heart defects.

There is limited evidence for loss-of-function as a mechanism of disease for either of these phenotypes.
Congenital Heart Defect v0.315 BRAF Penny Snell reviewed gene: BRAF: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: PMID: 19206169, 18042262; Phenotypes: Cardiofaciocutaneous syndrome, 115150, Noonan syndrome 7, 613706; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.315 GATA6 Sivaranjani Balachander reviewed gene: GATA6: Rating: GREEN; Mode of pathogenicity: None; Publications: (PMID: 22158542, 23223019, 23635550); Phenotypes: Congenital heart defects pancreatic agenesis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital Heart Defect v0.315 JAG1 Uditi Shah reviewed gene: JAG1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 26580007, 19325125, 11139239, 9207787, 9585603, 11152664, 32065591, 12022040, 20437614, 36400760); Phenotypes: ?Deafness, congenital heart defects, and posterior embryotoxon #617992, Alagille syndrome 1 #118450, Charcot-Marie-Tooth disease, axonal, type 2HH #619574, Tetralogy of Fallot #187500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.315 JAG1 Uditi Shah Deleted their review
Congenital Heart Defect v0.315 JAG1 Uditi Shah changed review comment from: JAG1 is a gene that plays a crucial role in capillary morphogenesis, mesenchymal stem cell differentiation into cardiomyocytes, and the regulation of signaling pathways such as Notch and Wnt.

Mutations in the JAG1 gene are associated with Alagille Syndrome (ALGS), a disorder characterized by liver, heart, and other organ abnormalities. ALGS exhibits high genetic heterogeneity, with various types of mutations identified, including deletions, insertions, splice site mutations, and missense mutations. The majority of ALGS cases involve haploinsufficiency, where a single functional copy of the JAG1 gene is insufficient for normal development. However, some missense mutations may act in a dominant-negative manner, inhibiting Notch signaling.

In TOF, a missense mutation in JAG1 was identified in a kindred segregating autosomal dominant TOF with variable expressivity and characteristic facial features.

JAG1 mutations in axonal Charcot-Marie-Tooth disease type 2HH were associated with impaired peripheral nerve integrity and altered Notch signaling.

Another syndrome, DCHE, involving hearing loss, congenital heart defects, and posterior embryotoxon, was also linked to a JAG1 missense mutation. (PMID: 12022040 PMID: 20437614 PMID: 36400760); to: JAG1 is a gene that plays a crucial role in capillary morphogenesis, mesenchymal stem cell differentiation into cardiomyocytes, and the regulation of signaling pathways such as Notch and Wnt. (PMID: 26580007, PMID: 19325125)

Mutations in the JAG1 gene are associated with Alagille Syndrome (ALGS), a disorder characterized by liver, heart, and other organ abnormalities. ALGS exhibits high genetic heterogeneity, with various types of mutations identified, including deletions, insertions, splice site mutations, and missense mutations. The majority of ALGS cases involve haploinsufficiency, where a single functional copy of the JAG1 gene is insufficient for normal development. However, some missense mutations may act in a dominant-negative manner, inhibiting Notch signaling. (PMID: 11139239, PMID: 9207787, PMID: 9585603)

In TOF, a missense mutation in JAG1 was identified in a kindred segregating autosomal dominant TOF with variable expressivity and characteristic facial features. (PMID: 11152664)

JAG1 mutations in axonal Charcot-Marie-Tooth disease type 2HH were associated with impaired peripheral nerve integrity and altered Notch signaling. (PMID: 32065591)

Another syndrome, DCHE, involving hearing loss, congenital heart defects, and posterior embryotoxon, was also linked to a JAG1 missense mutation. (PMID: 12022040 PMID: 20437614 PMID: 36400760)
Congenital Heart Defect v0.315 JAG1 Uditi Shah reviewed gene: JAG1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 12022040 PMID: 20437614 PMID: 36400760; Phenotypes: ?Deafness, congenital heart defects, and posterior embryotoxon #617992, Alagille syndrome 1 #118450, Charcot-Marie-Tooth disease, axonal, type 2HH #619574, Tetralogy of Fallot #187500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.315 NUP188 GORJANA ROBEVSKA gene: NUP188 was added
gene: NUP188 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: NUP188 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP188 were set to PMID: 32021605; 32275884
Phenotypes for gene: NUP188 were set to Sandestig-Stefanova syndrome MIM 618804
Review for gene: NUP188 was set to GREEN
Added comment: Sandestig et al 2020/19:
two unrelated female infants from consanguineous families, each with homozygous nonsense gene variants of NUP188 (p.Tyr96* and p.Gln113*, respectively). Both patients showed close similarity and specificity of clinical features including the course of the disease and a poor prognosis.

Muir et al 2020:
Four unrelated families with six affected female infants with bi-allelic truncating variants in NUP188. all found to have very similar phenotypes
Functional studies showed:
1. Nuclear import of proteins was decreased in affected individuals’ fibroblasts, supporting a possible disease mechanism.
2. CRISPR-mediated knockout of NUP188 in Drosophila revealed motor deficits and seizure susceptibility, partially recapitulating the neurological phenotype seen in affected individuals.
3. Removal of NUP188 also resulted in aberrant dendrite tiling, suggesting a potential role of NUP188 in dendritic development

Key clinical features of Sandestig-Stefanova syndrome MIM 618804:
- congenital cataracts
- hypotonia,
- prenatal-onset ventriculomegaly,
- white-matter abnormalities,
- hypoplastic corpus callosum,
- congenital heart defects, and
- central hypoventilation. 
Characteristic dysmorphic features include:
- small palpebral fissures,
- a wide nasal bridge and nose,
- micrognathia, and
- digital anomalies.
Sources: Literature
Congenital Heart Defect v0.315 CHST14 Arthur Limawan reviewed gene: CHST14: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ehlers-Danlos syndrome, arterial septal defects, coarctation of the aorta, patent ductus arteriosus, dextrocardia, tricuspid atresia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.315 MAP3K7 Emma Northrop gene: MAP3K7 was added
gene: MAP3K7 was added to Congenital Heart Defect. Sources: Other
Mode of inheritance for gene: MAP3K7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAP3K7 were set to PMID: 27426734; 29467388; 35730652; 27426733
Phenotypes for gene: MAP3K7 were set to Cardiospondylocarpofacial syndrome (CSCF) MIM# 157800; Frontometaphyseal dysplasia 2 (FMD2) MIM# 617137
Review for gene: MAP3K7 was set to GREEN
Added comment: CSCF - primarily caused by loss of function variants.
FMD2 - primarily caused by gain of function variants.

PMID: 27426734 - Monoallelic missense and in-frame deletion variants were identified in the MAP3K7 gene in six individuals affected with CSCF from four unrelated families. All met the clinical feature criteria of CSCF, including skeletal and facial features, and cardiac defects (including VSD (1/6), ASD (1/6) and valve dysplasia (6/6)). One family with 3 affected individuals across 2 generations was reported.

PMID: 29467388 - One case with a splice variant creating a new splice acceptor site causing an in-frame insertion of 2 amino acids. A heart ultrasound at birth revealed patent foramen ovale with left-right shunt and two small muscular ventricular septal defects, mitral and tricuspid valves dysplasia and mild, non-progressive aortic arch hypoplasia.

PMID: 35730652 - 14 novel patients with CSCF + 2 with FMD2. 9/15 with Congenital Heart Defects (including the 2 cases with FMD2), 2/12 Ventricular septal defects, 1/13 Atrial septal defects, 4/14 Cardiomyopathy. CSCF cases include one family with 2 individuals across 2 generations.
Sources: Other
Congenital Heart Defect v0.315 ARID1A Mary Huang reviewed gene: ARID1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 33803261; Phenotypes: Coffin-Siris syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.315 CRELD1 Rajini Sreenivasan reviewed gene: CRELD1: Rating: RED; Mode of pathogenicity: None; Publications: (PMID: 22740159, 12632326, 23040494, 25328912, 24697899, 33773999); Phenotypes: Atrioventricular septal defect, susceptibility to, 2, Atrioventricular septal defect, partial, with heterotaxy syndrome MIM#606217; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital Heart Defect v0.315 PIGV Jen Malcolm gene: PIGV was added
gene: PIGV was added to Congenital Heart Defect. Sources: Other
Mode of inheritance for gene: PIGV was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGV were set to PMID: 37372388; 24129430; 37390992; 20802478
Phenotypes for gene: PIGV were set to mental retardation; seizures and hypotonia; hyperphosphatasia; facial dysmorphism; variable degrees of brachytelephalangy
Penetrance for gene: PIGV were set to unknown
Mode of pathogenicity for gene: PIGV was set to Other
Review for gene: PIGV was set to RED
Added comment: Autosomal recessive. Multiple variants involved in Mabry syndrome (also known as Hyperphosphatasia)- intellectual disability, distinctive facial features, increased levels of an enzyme called alkaline phosphatase in the blood and other signs and symptoms.
Literature:
• Xue et al PMID: 27177984 2 Chinese infants with Mabry syndrome variants PIGV:c.615C>G (p.Asn205Lys) and c.854A>G (p.Tyr285Cys)
• Thompson et al, PMID: 22315194
3 patients (2 sibs with compound heterozygotes for c.467G > A and c.494C > A (novel variant) in exon 3 of PIGV gene. 3rd unrelated individual compound heterozygote for the known c.1022C > A/c.1022C > T (p.Ala341Glu/p.Ala341Val) mutation)
• Hutny et al PMID: 37372388, 6 Polish Patients all with homozygotic mutation (c.1022C>A; p.Ala341Glu) variant hyperphosphatasia with impaired intellectual development syndrome 1 (HPMRS1), distinct from other CDGs in terms of hyperphosphatemia related to abnormal ALP activity and brachytelephalangy.
• Horn et al PMID: 24129430
16 individuals with Mabrys syndrome, most common variant c.1022C>A , and also novel variants (c. 176T>G, c.53G>A, c.905T>C, and c.1405C>T) detected PIGV mutations and demonstrate that the severe end of the clinical spectrum presents as a multiple congenital malformation syndrome with a high frequency of Hirschsprung disease, vesicoureteral, and renal anomalies as well as anorectal malformations. PIGV mutations are the major cause of HPMRS, which displays a broad clinical variability regarding associated malformations and growth patterns. Severe developmental delays, particular facial anomalies, brachytelephalangy, and hyperphosphatasia are consistently found in PIGV-positive individuals.
No evidence of congenital heart defects found.
Sources: Other
Congenital Heart Defect v0.315 KDR Dee Lawlor reviewed gene: KDR: Rating: AMBER; Mode of pathogenicity: None; Publications: 34113005; Phenotypes: Tetralogy of Fallot; Mode of inheritance: Unknown
Congenital Heart Defect v0.315 KDR Dee Lawlor Deleted their review
Congenital Heart Defect v0.315 KDR Dee Lawlor reviewed gene: KDR: Rating: AMBER; Mode of pathogenicity: None; Publications: 34113005; Phenotypes: ; Mode of inheritance: Unknown
Congenital Heart Defect v0.315 PIGL Harshini Thiyagarajah reviewed gene: PIGL: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22444671; Phenotypes: colobomas, heart defects, ichthyosiform dermatosis, intellectual disability, ear anomalies; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.315 WASHC5 Lucas Mitchell gene: WASHC5 was added
gene: WASHC5 was added to Congenital Heart Defect. Sources: ClinGen,Literature
Mode of inheritance for gene: WASHC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WASHC5 were set to PMID: 24065355; 37840956; 30896870; 32349777; 32349777
Phenotypes for gene: WASHC5 were set to Ritscher-Schinzel syndrome - MIM#220210; Ventricular septal defect; Atrial septal defect; Tetralogy of Fallot; Double outlet right ventricle; Hypoplastic left heart; Aortic stenosis; Pulmonic stenosis
Penetrance for gene: WASHC5 were set to unknown
Review for gene: WASHC5 was set to AMBER
Added comment: Homozygous/biallelic variants in WASHC5 (previous name KIAA0196) are associated with Ritscher-Schinzel syndrome (RSS) - A developmental malformation syndrome characterised by craniofacial abnormalities, congenital heart defects, and cerebellar brain malformations. Cardiac defects include septal defects and aortic stenosis, among others (OMIM: Leonardi et al., 2001; Elliott et al., 2013).

Victor Chang CHD gene registry reports on WASHC5, also stating unknown penetrance.
(https://chdgene.victorchang.edu.au/gene/9897)

Literature (humans):
Elliot et al, 2013 (24065355)
8 first nations patients, and 8 of their parents, and 5 unaffected people from same geographic region (northern Manitoba, Canada) underwent homozygosity mapping by SNP array and sanger sequencing. Variable phenotypic traits among affected members included atrial and ventricular septal defects. The only biallelic mutations identified occurred in KIAA0196 (WASHC5), where sequence analysis revealed homozygosity for three novel variants (c.3335+2T>A, c.3335 +4C>A and c.3335+8A>G) in each patient (figure 2A). All parents were heterozygous for the three sequence changes, and none of the five control subjects was homozygous for any of these changes. Comparison of normalised cycle threshold (Ct) values indicated a 6.98 to 8.72 (mean 7.85)-fold reduction in the relative amount of KIAA0196 transcript in the patient samples versus the control sample. Sanger sequencing of the cloned PCR product from a patient revealed that the primary product did not contain exon 27 (figure 2B). Suggesting altered KIAA0196 transcript produced by the patient might be targeted for nonsense mediated decay. Strumpellin, the product of KIAA0196, is a highly conserved glycoprotein from plants to humans, and ubiquitously expressed.

Harvey et al, 2023 (37840956), reports 2 probands with WASHC5 variants and CHD phenotype. Not clear if probands related, or from same geographical area. Zygosity not clear. No information provided about probands, family testing/segregation.
Landis 2023, (37681527) a cohort of 1362 with CHD, reports one with variant in WASHC5. No further information provided about variant, zygosity, or about participant in paper or supp data.
Bu. 2020 et al, (30896870)
Reports, 9mnth male in Changsha, China, with patent ductus arteriosus (PDA) - an opening between two blood vessels leading from the heart, patent foramen ovale (PFO) - hole between the left and right atria, and KIAA0196 (WASHC5) variant. No mention zygosity or biallelic. No supp data provided.
Møller Nielsen, 2021(https://doi.org/10.1016/j.ijcchd.2021.100164),
Danish cohort study with Atrial septal defects (ASD), 384 variants identified, three WASHC5 variants are considered pathogenic. Supplementary table 3 reports three WASHC5 variants, but no further information is provided about participants, zygosity of variants, or if blood-related. Limitations state only had singleton data and unable to clarify inheritance/de-novo. Supplementary table reported further info for the three WASHC5 variants, but no explicit mention if biallelic mutations. Excel column J reports 'reads (Ref:Alt)' and indicates participants are ?heterozygous variants which may conflict with RSS being a recessive/biallelic condition?
Hseih, 2020, (32349777)
Mentioned having two damaging germline and one mosaic mutations in their cohort that supports WASHC5 to be a candidate CHD gene. No further information about those variants or participants is provided. No supp data provided.

Animal models:
Mouse Genome Informatics MGI#2146110) : Homozygous knockout mice die well prior to E13.5 as no evidence of conceptus. In heterozygous knockout mice no cardiovascular defect recorded.
Bu, 2020 (32417190)
Mouse and zebrafish studies show potential evidence for WASHC5 biallelic variants cause CHD/. However CliniGen Commented "neither provide evidence to support the gene-disease relationship (Bu et al., PMID:32417190)"


In summary, Elliot et al provides detailed evidence, however looking further at recent literature, studies mention or report on WASHC5 variants and possible associations with CHD, but do not report enough detail to be confident and satisfy ClinGene/PanelApp criteria.
Sources: ClinGen, Literature
Congenital Heart Defect v0.315 PIGL Harshini Thiyagarajah gene: PIGL was added
gene: PIGL was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: PIGL was set to BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.315 ARID1A Kaitlyn Dianna Weldon reviewed gene: ARID1A: Rating: GREEN; Mode of pathogenicity: None; Publications: NBK131811; Phenotypes: Coffin-Siris syndrome MONDO:0015452; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.315 TXNL4A LUCAS GARCIA ALVES FERREIRA gene: TXNL4A was added
gene: TXNL4A was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: TXNL4A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TXNL4A were set to 25434003; 28905882
Phenotypes for gene: TXNL4A were set to Burn-McKeown syndrome - MIM#608572
Penetrance for gene: TXNL4A were set to unknown
Review for gene: TXNL4A was set to AMBER
Added comment: Homozygous or compound heterozygous mutation in the TXNL4A gene are associated to Burn-McKeown syndrome (BMKS). BMKS is a rare disorder in which individuals with normal intellectual development exhibit the characteristic combination of choanal atresia, sensorineural deafness, cardiac defects, and typical craniofacial dysmorphism consisting of narrow palpebral fissures, coloboma of the lower eyelids, prominent nose with high nasal bridge, short philtrum, cleft lip and/or palate, and large and protruding ears (Wieczorek et al 2014 - PMID 25434003).

Wieczorek et al (2014 - PMID: 25434003) report 9 families presenting individuals with BMKS and harboring biallelic variants in the TXNL4A gene. Four unrelated individuals presented cardiac defects.

Goos et al (2017 - PMID: 28905882) report an individual with BMKS including asymptomatic atrial and ventricular septal defects, and harboring biallelic variants in the TXNL4A gene.
Sources: Literature
Congenital Heart Defect v0.315 SMG9 Laura S Deleted their comment
Congenital Heart Defect v0.315 SMG9 Laura S edited their review of gene: SMG9: Added comment: Autosomal recessive inheritance

Shaheen et al. in 2016 (27018474) published case reports about two consanguineous families in which a similar patter of congenital anomalies was found to be most likely caused by homozygous loss-of-function mutation in SMG9. This gene encodes an essential component of the SURF complex that generates phosphor-UPF1, the single most important step in nonsense-mediated decay (NMD). The authors generated a knock-out Smg9 mouse model using CRISPR/Cas9 and observed similar congenital anomaly syndrome to the one reported in humans. Additionally, human cells not expressing SMG9 had global transcriptional dysregulation, but not reduction of premature stop codon (PST)-containing transcripts.

The affected family members in these two families showed to have phenotypic overlap between Dandy-Walker malformation and congenital heart disease. Due to the consanguineous nature in both families and the geographical proximity (both cases in Arabia) indicate the possibility of a homozygous pathogenic variants in the same gene. These variants are c.520_521delCC and c.701+4A>G, both affecting the gene SMG9. The indel in family 1 predicts a frameshift and premature truncation, p.Pro174Argfs*12. In family 2, a complete skipping of exon 6 was revealed by RT-PCR. The resulting aberrant transcript predicts frameshift and premature truncation (p.Tyr197Aspfs*10).

In 2019, another case was reported by Lecoquierre et al. (31390136). The patient presented with a syndromic association of severe global developmental delay and diverse malformations. She carried a novel SMG9 homozygous variant NM_019108.3:c.1177C>T, p.(Gln393*), while her unaffected parents were both heterozygous and first-degree cousins. This absent variant in gnomaAD was predicted to result in a premature stop codon leading to nonsense-mediated decay within this single transcript gene.

In 2020, Lemire et al. (32412169) reported a case of 7-year-old female with severe intellectual disability, multiple congenital anomalies, including cardiovascular anomalies, and facial dysmorphisms. No known consanguinity, the parents were heterozygous for the variant and she had an unaffected brother. She carried a homozygous missense variant in the SMG9 gene (c.1508G > C; p.Trp503Ser) identified as the likely etiology. In silico analysis predicted this change to impact protein structure/function. This missense change is rare, with only one allele count in gnomAD and no homozygotes.

In 2021, Altuwaijri et al. (33609422) reported a new case in a research letter to the editor, in which a 25-month-old male had significant heart and brain malformations. Exome sequencing performed on the subject revealed the same homozygous splicing variant (NM_019108.4: exon7:c.701+4A>G) as their original report (Shaheen et al., 2016). Thus validating their previous findings.; Changed publications: 27018474 31390136 32412169 33609422; Changed phenotypes: Heart and brain malformation syndrome (HBMS)
Congenital Heart Defect v0.315 SMG9 Laura S changed review comment from: Autosomal recessive inheritance

Shaheen et al. in 2016 (27018474) published case reports about two consanguineous families in which a similar patter of congenital anomalies was found to be most likely caused by homozygous loss-of-function mutation in SMG9. This gene encodes an essential component of the SURF complex that generates phosphor-UPF1, the single most important step in nonsense-mediated decay (NMD). The authors generated a knock-out Smg9 mouse model using CRISPR/Cas9 and observed similar congenital anomaly syndrome to the one reported in humans. Additionally, human cells not expressing SMG9 had global transcriptional dysregulation, but not reduction of premature stop codon (PST)-containing transcripts.

The affected family members in these two families showed to have phenotypic overlap between Dandy-Walker malformation and congenital heart disease. Due to the consanguineous nature in both families and the geographical proximity (both cases in Arabia) indicate the possibility of a homozygous pathogenic variants in the same gene. These variants are c.520_521delCC and c.701+4A>G, both affecting the gene SMG9. The indel in family 1 predicts a frameshift and premature truncation, p.Pro174Argfs*12. In family 2, a complete skipping of exon 6 was revealed by RT-PCR. The resulting aberrant transcript predicts frameshift and premature truncation (p.Tyr197Aspfs*10).

In 2019, another case was reported by Lecoquierre et al. (31390136). The patient presented with a syndromic association of severe global developmental delay and diverse malformations. She carried a novel SMG9 homozygous variant NM_019108.3:c.1177C>T, p.(Gln393*), while her unaffected parents were both heterozygous and first-degree cousins. This absent variant in gnomaAD was predicted to result in a premature stop codon leading to nonsense-mediated decay within this single transcript gene.

In 2020, Lemire et al. (32412169) reported a case of 7-year-old female with severe intellectual disability, multiple congenital anomalies, including cardiovascular anomalies, and facial dysmorphisms. No known consanguinity, the parents were heterozygous for the variant and she had an unaffected brother. She carried a homozygous missense variant in the SMG9 gene (c.1508G > C; p.Trp503Ser) identified as the likely etiology. In silico analysis predicted this change to impact protein structure/function. This missense change is rare, with only one allele count in gnomAD and no homozygotes.

In 2021, Altuwaijri et al. (33609422) reported a new case in a research letter to the editor, in which a 25-month-old male had significant heart and brain malformations. Exome sequencing performed on the subject revealed the same homozygous splicing variant (NM_019108.4: exon7:c.701+4A>G) as their original report (Shaheen et al., 2016). Thus validating their previous findings.
Sources: Literature; to: Autosomal recessive inheritance

Shaheen et al. in 2016 (27018474) published case reports about two consanguineous families in which a similar patter of congenital anomalies was found to be most likely caused by homozygous loss-of-function mutation in SMG9. This gene encodes an essential component of the SURF complex that generates phosphor-UPF1, the single most important step in nonsense-mediated decay (NMD). The authors generated a knock-out Smg9 mouse model using CRISPR/Cas9 and observed similar congenital anomaly syndrome to the one reported in humans. Additionally, human cells not expressing SMG9 had global transcriptional dysregulation, but not reduction of premature stop codon (PST)-containing transcripts.

The affected family members in these two families showed to have phenotypic overlap between Dandy-Walker malformation and congenital heart disease. Due to the consanguineous nature in both families and the geographical proximity (both cases in Arabia) indicate the possibility of a homozygous pathogenic variants in the same gene. These variants are c.520_521delCC and c.701+4A>G, both affecting the gene SMG9. The indel in family 1 predicts a frameshift and premature truncation, p.Pro174Argfs*12. In family 2, a complete skipping of exon 6 was revealed by RT-PCR. The resulting aberrant transcript predicts frameshift and premature truncation (p.Tyr197Aspfs*10).

In 2019, another case was reported by Lecoquierre et al. (31390136). The patient presented with a syndromic association of severe global developmental delay and diverse malformations. She carried a novel SMG9 homozygous variant NM_019108.3:c.1177C>T, p.(Gln393*), while her unaffected parents were both heterozygous and first-degree cousins. This absent variant in gnomaAD was predicted to result in a premature stop codon leading to nonsense-mediated decay within this single transcript gene.

In 2020, Lemire et al. (32412169) reported a case of 7-year-old female with severe intellectual disability, multiple congenital anomalies, including cardiovascular anomalies, and facial dysmorphisms. No known consanguinity, the parents were heterozygous for the variant and she had an unaffected brother. She carried a homozygous missense variant in the SMG9 gene (c.1508G > C; p.Trp503Ser) identified as the likely etiology. In silico analysis predicted this change to impact protein structure/function. This missense change is rare, with only one allele count in gnomAD and no homozygotes.

In 2021, Altuwaijri et al. (33609422) reported a new case in a research letter to the editor, in which a 25-month-old male had significant heart and brain malformations. Exome sequencing performed on the subject revealed the same homozygous splicing variant (NM_019108.4: exon7:c.701+4A>G) as their original report (Shaheen et al., 2016). Thus validating their previous findings.
Sources: Literature
Congenital Heart Defect v0.315 SMG9 Laura S gene: SMG9 was added
gene: SMG9 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: SMG9 was set to Other
Publications for gene: SMG9 were set to 27018474
Review for gene: SMG9 was set to RED
Added comment: Autosomal recessive inheritance

Shaheen et al. in 2016 (27018474) published case reports about two consanguineous families in which a similar patter of congenital anomalies was found to be most likely caused by homozygous loss-of-function mutation in SMG9. This gene encodes an essential component of the SURF complex that generates phosphor-UPF1, the single most important step in nonsense-mediated decay (NMD). The authors generated a knock-out Smg9 mouse model using CRISPR/Cas9 and observed similar congenital anomaly syndrome to the one reported in humans. Additionally, human cells not expressing SMG9 had global transcriptional dysregulation, but not reduction of premature stop codon (PST)-containing transcripts.

The affected family members in these two families showed to have phenotypic overlap between Dandy-Walker malformation and congenital heart disease. Due to the consanguineous nature in both families and the geographical proximity (both cases in Arabia) indicate the possibility of a homozygous pathogenic variants in the same gene. These variants are c.520_521delCC and c.701+4A>G, both affecting the gene SMG9. The indel in family 1 predicts a frameshift and premature truncation, p.Pro174Argfs*12. In family 2, a complete skipping of exon 6 was revealed by RT-PCR. The resulting aberrant transcript predicts frameshift and premature truncation (p.Tyr197Aspfs*10).

In 2019, another case was reported by Lecoquierre et al. (31390136). The patient presented with a syndromic association of severe global developmental delay and diverse malformations. She carried a novel SMG9 homozygous variant NM_019108.3:c.1177C>T, p.(Gln393*), while her unaffected parents were both heterozygous and first-degree cousins. This absent variant in gnomaAD was predicted to result in a premature stop codon leading to nonsense-mediated decay within this single transcript gene.

In 2020, Lemire et al. (32412169) reported a case of 7-year-old female with severe intellectual disability, multiple congenital anomalies, including cardiovascular anomalies, and facial dysmorphisms. No known consanguinity, the parents were heterozygous for the variant and she had an unaffected brother. She carried a homozygous missense variant in the SMG9 gene (c.1508G > C; p.Trp503Ser) identified as the likely etiology. In silico analysis predicted this change to impact protein structure/function. This missense change is rare, with only one allele count in gnomAD and no homozygotes.

In 2021, Altuwaijri et al. (33609422) reported a new case in a research letter to the editor, in which a 25-month-old male had significant heart and brain malformations. Exome sequencing performed on the subject revealed the same homozygous splicing variant (NM_019108.4: exon7:c.701+4A>G) as their original report (Shaheen et al., 2016). Thus validating their previous findings.
Sources: Literature
Congenital Heart Defect v0.315 DOCK6 Zornitza Stark Marked gene: DOCK6 as ready
Congenital Heart Defect v0.315 DOCK6 Zornitza Stark Gene: dock6 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.315 DOCK6 Zornitza Stark Phenotypes for gene: DOCK6 were changed from to Adams-Oliver syndrome 2 MIM#614219
Congenital Heart Defect v0.314 DOCK6 Zornitza Stark Publications for gene: DOCK6 were set to
Congenital Heart Defect v0.314 DOCK6 Zornitza Stark Mode of inheritance for gene: DOCK6 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.313 DOCK6 Zornitza Stark edited their review of gene: DOCK6: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.313 DOCK6 Zornitza Stark reviewed gene: DOCK6: Rating: GREEN; Mode of pathogenicity: None; Publications: 28160419; Phenotypes: Adams-Oliver syndrome 2 MIM#614219; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.313 DOCK6 Richard McCoy reviewed gene: DOCK6: Rating: RED; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: PMID: 21820096, 23522784, 7606848, 25824905, 25824905, 36789878; Phenotypes: neurological disorders, impaired intellectual development, microcephaly, aplasia cutis congenita, terminal transverse limb defects; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.313 GATA5 Ceecee Britten-Jones reviewed gene: GATA5: Rating: AMBER; Mode of pathogenicity: None; Publications: 21633169, 21839733, 23289003, 22961344, 24638895, 2329559, 23040494, 25515806, 35534675, 22641149, 26708639; Phenotypes: 617912; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital Heart Defect v0.313 CHD4 Zornitza Stark Marked gene: CHD4 as ready
Congenital Heart Defect v0.313 CHD4 Zornitza Stark Gene: chd4 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.313 CHD4 Zornitza Stark Phenotypes for gene: CHD4 were changed from to Sifrim-Hitz-Weiss syndrome (MIM#617159)
Congenital Heart Defect v0.312 CHD4 Zornitza Stark Publications for gene: CHD4 were set to
Congenital Heart Defect v0.311 CHD4 Zornitza Stark Mode of inheritance for gene: CHD4 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.310 CHD4 Polly McIntosh changed review comment from: OMIM 617159 Sifrim-Hitz-Weiss Syndrome (Also called CHD4 Neurodevelopmental Disorder)
31 de novo cases with Sifrim-Hitz-Weiss Syndrome PMID 31388190:
72% of patients assessed (21/29) had structural heart abnormalities inc. septal defects, tetrology of Fallot and truncus arteriosus.
Functional studies on engineered cells with CHD4 variants showed reduced ATPase activity and reduced chromatin remodeling (PMID 31388190). Mouse studies on another CHD4 variant showed ventricular hypertrabeculation in CHD4 variant mice (PMID 37254794); to: OMIM 617159 Sifrim-Hitz-Weiss Syndrome (Also called CHD4 Neurodevelopmental Disorder)
31 de novo cases with Sifrim-Hitz-Weiss Syndrome PMID 31388190:
72% of patients assessed (21/29) had structural heart abnormalities inc. septal defects, tetrology of Fallot and truncus arteriosus.
Functional studies on engineered cells with CHD4 variants showed reduced ATPase activity and reduced chromatin remodeling (PMID 31388190). Mouse studies on another CHD4 variant showed ventricular hypertrabeculation in CHD4 variant mice (PMID 37254794)
Congenital Heart Defect v0.310 CHD4 Polly McIntosh reviewed gene: CHD4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31388190, 31474762, 27479907, 27616479, 24348274, 37254794; Phenotypes: Developmental delay, intellectual disability, ophthalmological abnormalities, congenital heart defects, hypotonia, hearing impairment, cryptorchidism, macrocephaly, skeletal abnormalities, hypogonadism, short stature, hydrocephalus; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.310 LZTR1 Zornitza Stark Mode of inheritance for gene: LZTR1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital Heart Defect v0.309 LZTR1 Zornitza Stark Classified gene: LZTR1 as Green List (high evidence)
Congenital Heart Defect v0.309 LZTR1 Zornitza Stark Gene: lztr1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.308 LZTR1 Zornitza Stark reviewed gene: LZTR1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Noonan syndrome 10, MIM# 616564, Noonan syndrome 2, MIM# 605275; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital Heart Defect v0.308 LZTR1 Emanuel Birru gene: LZTR1 was added
gene: LZTR1 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: LZTR1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LZTR1 were set to PMID: 30368668; 34184824
Phenotypes for gene: LZTR1 were set to Cardiac defects; hypertrophic cardiomyopathy; atrial septal defect; pulmonary stenosis; short stature; intellectual disabilities
Penetrance for gene: LZTR1 were set to Incomplete
Review for gene: LZTR1 was set to GREEN
Added comment: Several variants of LZTR1 demonstrate compound heterozygosity, implying an autosomal recessive mode of inheritance. Patients with LZTR1 variants had cardiac defects, and these LZTR1 variants are linked to a spectrum of conditions, including Noonan syndrome (NS), Costello syndrome, cardiofaciocutaneous syndrome, and other related disorders.

Many patients carrying LZTR1 variants are clinically suspected to have Noonan syndrome due to the presence of shared clinical features associated with NS. These features encompass relative macrocephaly, NS-associated facial characteristics, heart defects, intellectual disability, and short stature.
Sources: Literature
Congenital Heart Defect v0.308 MYH11 Zoe Ward reviewed gene: MYH11: Rating: AMBER; Mode of pathogenicity: Other; Publications: 27418595, 16444274, 21937134, 17666408, 22968129, 37306888; Phenotypes: Patent Ductus Arteriosus (PDA); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital Heart Defect v0.308 EFTUD2 Zornitza Stark Marked gene: EFTUD2 as ready
Congenital Heart Defect v0.308 EFTUD2 Zornitza Stark Gene: eftud2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.308 EFTUD2 Zornitza Stark Phenotypes for gene: EFTUD2 were changed from to Mandibulofacial dysostosis, Guion-Almeida type (MIM#610536; MONDO:0012516)
Congenital Heart Defect v0.307 EFTUD2 Zornitza Stark Publications for gene: EFTUD2 were set to
Congenital Heart Defect v0.306 EFTUD2 Zornitza Stark Mode of inheritance for gene: EFTUD2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.305 RERE Zornitza Stark Marked gene: RERE as ready
Congenital Heart Defect v0.305 RERE Zornitza Stark Gene: rere has been classified as Green List (High Evidence).
Congenital Heart Defect v0.305 RERE Zornitza Stark Publications for gene: RERE were set to 29330883, 27087320, 33772547, 36053530
Congenital Heart Defect v0.304 RERE Zornitza Stark Classified gene: RERE as Green List (high evidence)
Congenital Heart Defect v0.304 RERE Zornitza Stark Gene: rere has been classified as Green List (High Evidence).
Congenital Heart Defect v0.303 RERE Julia Broadbent gene: RERE was added
gene: RERE was added to Congenital Heart Defect. Sources: Literature,ClinGen
Mode of inheritance for gene: RERE was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RERE were set to 29330883, 27087320, 33772547, 36053530
Phenotypes for gene: RERE were set to Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (OMIM #616975)
Penetrance for gene: RERE were set to Complete
Review for gene: RERE was set to GREEN
Added comment: Niehaus, Kim & Manning (2022) (PMID: 36053530) provide an updated literature review, and assert 23 cases have been reported of Neurodevelopmental Disorders with or without Anomalies of the Brain, Eye, or Heart (NEDBEH) caused by heterozygous pathogenic variants in RERE. Eleven of the 23 patients reported (48%) had congenital heart disease, most commonly septal disease. All variants were de novo except one, inherited from a mother with mild symptoms. Variant types include missense, frameshift, small deletions & duplications and 1 large deletion. Missense variants in the atrophin-1 domain seem to present with a more severe phenotype than loss-of-function variants

NEDBEH is fully penetrant but has variable expressivity – congenital heart anomalies not always present.

ClinGen: definitive association with AD complex neurodevelopmental disorder with or without congenital anomalies.
Sources: Literature, ClinGen
Congenital Heart Defect v0.303 GDF1 Zornitza Stark Marked gene: GDF1 as ready
Congenital Heart Defect v0.303 GDF1 Zornitza Stark Gene: gdf1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.303 GDF1 Zornitza Stark Phenotypes for gene: GDF1 were changed from to Congenital heart defects, multiple types, 6 MIM#613854
Congenital Heart Defect v0.302 GDF1 Zornitza Stark Publications for gene: GDF1 were set to
Congenital Heart Defect v0.301 GDF1 Zornitza Stark Mode of inheritance for gene: GDF1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.300 GDF1 Ting Chan edited their review of gene: GDF1: Changed phenotypes: Congenital heart defects, multiple types, 6 MIM#613854
Congenital Heart Defect v0.300 GDF1 Ting Chan edited their review of gene: GDF1: Changed publications: 33131162, 35351224, 32144877
Congenital Heart Defect v0.300 GDF1 Ting Chan reviewed gene: GDF1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33131162, 35351224, 32144877; Phenotypes: 613854; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.300 EFTUD2 Sangavi Sivagnanasundram reviewed gene: EFTUD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23879989, 32315467; Phenotypes: Mandibulofacial dysostosis, Guion-Almeida type (MIM#610536, MONDO:0012516); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.300 CHD7 Zornitza Stark Marked gene: CHD7 as ready
Congenital Heart Defect v0.300 CHD7 Zornitza Stark Gene: chd7 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.300 CHD7 Zornitza Stark Phenotypes for gene: CHD7 were changed from to CHARGE syndrome (MIM# 214800)
Congenital Heart Defect v0.299 CHD7 Zornitza Stark Publications for gene: CHD7 were set to
Congenital Heart Defect v0.298 CHD7 Zornitza Stark Mode of inheritance for gene: CHD7 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.297 HAND2 Zornitza Stark Phenotypes for gene: HAND2 were changed from Congenital heart disease to Congenital heart disease, MONDO:0005453, HAND2-related
Congenital Heart Defect v0.296 HAND2 Zornitza Stark Publications for gene: HAND2 were set to 26865696; 32134193; 26676105; 30217752; 20819618
Congenital Heart Defect v0.295 HAND2 Chris McEvoy changed review comment from: Single additional relevant reports detailing associations between HAND2 variants and cardiac defects published since previous review (Jan 2022). No segregation analysis, de nova mutation is large deletion encompassing 3 genes:
PMID: 36427970 Chen et al 2022. Prenatal detection of de novo 17.8Mb deletion of 4q34.1→qter including HAND2, SORBS2 and DUX4. Associated with low pregnancy associated plasma protein-A (PAPP-A) and low placental growth factor (PlGF) in the first-trimester maternal serum screening, congenital heart defect (CHD) on fetal ultrasound and a false negative non-invasive prenatal testing (NIPT) result.

No pathogenic variants listed in Clinvar apart from p.(Glu67*) - see previously reviewed PMID:30217752.

Insufficient additional evidence to change gene rating from Amber.; to: Single additional relevant report detailing associations between HAND2 variants and cardiac defects published since previous review (Jan 2022). No segregation analysis, de novo mutation is large deletion encompassing 3 genes:
PMID: 36427970 Chen et al 2022. Prenatal detection of de novo 17.8Mb deletion of 4q34.1→qter including HAND2, SORBS2 and DUX4. Associated with low pregnancy associated plasma protein-A (PAPP-A) and low placental growth factor (PlGF) in the first-trimester maternal serum screening, congenital heart defect (CHD) on fetal ultrasound and a false negative non-invasive prenatal testing (NIPT) result.

No pathogenic variants listed in Clinvar apart from p.(Glu67*) - see previously reviewed PMID:30217752.

Insufficient additional evidence to change gene rating from Amber.
Congenital Heart Defect v0.295 CHD7 Purvi Kakadiya changed review comment from: De novo mutations in chromodomain helicase DNA binding protein 7 (CHD7) are cause CHARGE syndrome (MIM# 214800). The clinical phenotype of CHARGE syndrome is highly variable including a wide spectrum of congenital heart defects.
Thus, mutated CHD7 is associated with heart anomalies and therefore, CHD7 should be examined as part of genetic analysis (NGS gene panel) for congenital heart disease.; to: De novo mutations in chromodomain helicase DNA binding protein 7 (CHD7) are cause of CHARGE syndrome (MIM# 214800). The clinical phenotype of CHARGE syndrome is highly variable including a wide spectrum of congenital heart defects.
Thus, mutated CHD7 is associated with heart anomalies and therefore, CHD7 should be examined as part of genetic analysis (NGS gene panel) for congenital heart defect.
Congenital Heart Defect v0.295 CHD7 Purvi Kakadiya reviewed gene: CHD7: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31833191, 15300250, 16400610, 16155193, 17334995; Phenotypes: CHARGE syndrome (MIM# 214800); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.295 HAND2 Chris McEvoy reviewed gene: HAND2: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 36427970; Phenotypes: Congenital heart disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.295 KDM2B Ain Roesley edited their review of gene: KDM2B: Changed phenotypes: neurodevelopmental disorder MONDO#0700092, KDM2B-related
Congenital Heart Defect v0.295 KDM2B Ain Roesley Phenotypes for gene: KDM2B were changed from neurodevelopmental disorder MONDO#070009, KDM2B-related to neurodevelopmental disorder MONDO#0700092, KDM2B-related
Congenital Heart Defect v0.294 CUL3 Zornitza Stark Marked gene: CUL3 as ready
Congenital Heart Defect v0.294 CUL3 Zornitza Stark Gene: cul3 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.294 CUL3 Zornitza Stark Phenotypes for gene: CUL3 were changed from Neurodevelopmental disorder with or without autism or seizures (MIM#619239); Pseudohypoaldosteronism, type IIE (MIM#614496) to Neurodevelopmental disorder with or without autism or seizures (MIM#619239)
Congenital Heart Defect v0.293 CUL3 Zornitza Stark Classified gene: CUL3 as Green List (high evidence)
Congenital Heart Defect v0.293 CUL3 Zornitza Stark Gene: cul3 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.292 CUL3 Lucy Spencer gene: CUL3 was added
gene: CUL3 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: CUL3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CUL3 were set to 37665043
Phenotypes for gene: CUL3 were set to Neurodevelopmental disorder with or without autism or seizures (MIM#619239); Pseudohypoaldosteronism, type IIE (MIM#614496)
Review for gene: CUL3 was set to GREEN
Added comment: PMID: 37665043
1 case study and a review of the literature. 5 patients with de novo variants (PTCs and missense) in CUL3 who have various cardiac phenotypes: atrial septal defects, left ventricular outflow tract obstruction. Hypertrophic right ventricle pulmonary atresia, and other congenital heart defects. 2 of these patients have a neurological phenotype as well, while the other three are not reported to have one (but at least one was a terminated pregnancy).
Sources: Literature
Congenital Heart Defect v0.292 LAMA3 Bryony Thompson Marked gene: LAMA3 as ready
Congenital Heart Defect v0.292 LAMA3 Bryony Thompson Gene: lama3 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.292 LAMA3 Bryony Thompson Classified gene: LAMA3 as Amber List (moderate evidence)
Congenital Heart Defect v0.292 LAMA3 Bryony Thompson Gene: lama3 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.291 LAMA3 Bryony Thompson gene: LAMA3 was added
gene: LAMA3 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: LAMA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LAMA3 were set to 37635785
Phenotypes for gene: LAMA3 were set to Ebstein anomaly MONDO:0009144
Review for gene: LAMA3 was set to AMBER
Added comment: Single study with heterozygous nonsense variants identified in LAMA3 in two families with incomplete penetrance (a trio with one unaffected parent and a family with 2 affected and 1 unaffected carrier). p.Arg1126Ter has 5 hets in gnomAD v2.1 & p.Gln1507Ter has 4 hets in gnomAD v2.1. Variant filtering (including CNV detection algorithms) was conducted on WGS/WES from the trio and 2 affected individuals from the family.
Cardiac phenotypes in carriers of the junctional EB families harbouring LAMA3 pathogenic variants have not been reported. Lama3 +/- mice demonstrated abnormalities in the tricuspid valve and RV, similar to phenotypes observed in human Ebstein’s anomaly. Lama3 -/- mice were embryonic lethal.
Sources: Literature
Congenital Heart Defect v0.290 CTNNB1 Zornitza Stark Classified gene: CTNNB1 as Green List (high evidence)
Congenital Heart Defect v0.290 CTNNB1 Zornitza Stark Gene: ctnnb1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.290 CTNNB1 Zornitza Stark Marked gene: CTNNB1 as ready
Congenital Heart Defect v0.290 CTNNB1 Zornitza Stark Gene: ctnnb1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.290 CTNNB1 Zornitza Stark Marked gene: CTNNB1 as ready
Congenital Heart Defect v0.290 CTNNB1 Zornitza Stark Gene: ctnnb1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.290 CTNNB1 Zornitza Stark Classified gene: CTNNB1 as Green List (high evidence)
Congenital Heart Defect v0.290 CTNNB1 Zornitza Stark Gene: ctnnb1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.290 CTNNB1 Zornitza Stark Classified gene: CTNNB1 as Green List (high evidence)
Congenital Heart Defect v0.290 CTNNB1 Zornitza Stark Gene: ctnnb1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.289 CTNNB1 Zornitza Stark reviewed gene: CTNNB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with spastic diplegia and visual defects MIM#615075; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.289 CTNNB1 Lilian Downie gene: CTNNB1 was added
gene: CTNNB1 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: CTNNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CTNNB1 were set to PMID: 37455656
Phenotypes for gene: CTNNB1 were set to Neurodevelopmental disorder with spastic diplegia and visual defects MIM#615075
Added comment: Paper reviewing 19 patients; five cases presenting with different types of CHDs, including absent pulmonary valve (APV) with intact ventricular septum (IVS),
atrioventricular canal defect (AVCD), tetralogy of Fallot (ToF), and
mitral valve prolapse (MPV).
Lit review summarised about 25% of patients will have a cardiac anomaly as part of the phenotype.
Sources: Literature
Congenital Heart Defect v0.289 IFT74 Krithika Murali Marked gene: IFT74 as ready
Congenital Heart Defect v0.289 IFT74 Krithika Murali Gene: ift74 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.289 IFT74 Krithika Murali Classified gene: IFT74 as Green List (high evidence)
Congenital Heart Defect v0.289 IFT74 Krithika Murali Gene: ift74 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.288 IFT74 Naomi Baker gene: IFT74 was added
gene: IFT74 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: IFT74 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IFT74 were set to PMID: 37315079
Phenotypes for gene: IFT74 were set to Jeune syndrome (MONDO:0018770), IFT74-related
Added comment: Five individuals from four families reported. A homozygous exon 2 deletion was identified in two families, and splice variants were identified in the other two families (with minigene experiments demonstrating an effect on splicing of the non-canonical/deep intronic splice variants).

Four of the five individuals had heart defects, including ASD, AVSD, patent ductus arteriosus, double outlet right ventricle, hypoplastic left heart, aortic atresia, and hypoplastic left
ventricle.

Authors also characterised three mouse Ift74 alleles, with phenotypes ranging from a severe mid gestational lethal phenotype in the Ift74Tm1d out of frame exon 3 deletion allele, a post-natal lethal phenotype in the Ift74Tm1a exon 2 skip allele, to no detectable phenotype in Ift74Tm1b in frame exon 3 deletion allele.
Sources: Literature
Congenital Heart Defect v0.288 ZMYND10 Bryony Thompson Marked gene: ZMYND10 as ready
Congenital Heart Defect v0.288 ZMYND10 Bryony Thompson Gene: zmynd10 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.288 ZMYND10 Bryony Thompson Classified gene: ZMYND10 as Green List (high evidence)
Congenital Heart Defect v0.288 ZMYND10 Bryony Thompson Gene: zmynd10 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.287 ZMYND10 Bryony Thompson gene: ZMYND10 was added
gene: ZMYND10 was added to Congenital Heart Defect. Sources: Other
Mode of inheritance for gene: ZMYND10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZMYND10 were set to 23891471; 23891469; 29402277
Phenotypes for gene: ZMYND10 were set to Primary ciliary dyskinesia 22 MONDO:0014192
Review for gene: ZMYND10 was set to GREEN
gene: ZMYND10 was marked as current diagnostic
Added comment: CHD is a commonly reported feature of the condition.
Sources: Other
Congenital Heart Defect v0.286 Bryony Thompson Panel types changed to Victorian Clinical Genetics Services; Royal Melbourne Hospital; Rare Disease
Congenital Heart Defect v0.285 TTC25 Bryony Thompson Marked gene: TTC25 as ready
Congenital Heart Defect v0.285 TTC25 Bryony Thompson Gene: ttc25 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.285 TTC25 Bryony Thompson Classified gene: TTC25 as Green List (high evidence)
Congenital Heart Defect v0.285 TTC25 Bryony Thompson Gene: ttc25 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.284 TTC25 Bryony Thompson gene: TTC25 was added
gene: TTC25 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: TTC25 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC25 were set to 34215651; 33746037; 27486780
Phenotypes for gene: TTC25 were set to primary ciliary dyskinesia 35 MONDO:0014910
Review for gene: TTC25 was set to GREEN
Added comment: At least 3 probands reported with congenital heart defects and a supporting mouse model.
Sources: Literature
Congenital Heart Defect v0.283 MAP4K4 Zornitza Stark Marked gene: MAP4K4 as ready
Congenital Heart Defect v0.283 MAP4K4 Zornitza Stark Gene: map4k4 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.283 MAP4K4 Zornitza Stark Classified gene: MAP4K4 as Green List (high evidence)
Congenital Heart Defect v0.283 MAP4K4 Zornitza Stark Gene: map4k4 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.282 MAP4K4 Zornitza Stark gene: MAP4K4 was added
gene: MAP4K4 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: MAP4K4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAP4K4 were set to 37126546
Phenotypes for gene: MAP4K4 were set to RASopathy, MONDO:0021060, MAP4K4-related
Review for gene: MAP4K4 was set to GREEN
Added comment: 26 individuals from 21 families reported with Rasopathy-like phenotype, comprising ID/DD, dysmorphic features and congenital anomalies.
Sources: Literature
Congenital Heart Defect v0.281 POLR1A Elena Savva Classified gene: POLR1A as Green List (high evidence)
Congenital Heart Defect v0.281 POLR1A Elena Savva Gene: polr1a has been classified as Green List (High Evidence).
Congenital Heart Defect v0.280 POLR1A Elena Savva Marked gene: POLR1A as ready
Congenital Heart Defect v0.280 POLR1A Elena Savva Gene: polr1a has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.280 POLR1A Elena Savva gene: POLR1A was added
gene: POLR1A was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: POLR1A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: POLR1A were set to PMID: 37075751
Phenotypes for gene: POLR1A were set to Acrofacial dysostosis, Cincinnati type MIM#616462
Review for gene: POLR1A was set to GREEN
Added comment: PMID: 37075751 - 8/21 patients had congenital heart disease (mostly septal defect, one patient had bicuspid aortic valve, aortic aneurysm). Het mouse model had heart defects including truncus arteriosus
Sources: Literature
Congenital Heart Defect v0.280 POLR1A Elena Savva gene: POLR1A was added
gene: POLR1A was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: POLR1A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: POLR1A were set to PMID: 37075751
Phenotypes for gene: POLR1A were set to Acrofacial dysostosis, Cincinnati type MIM#616462
Review for gene: POLR1A was set to GREEN
Added comment: PMID: 37075751 - 8/21 patients had congenital heart disease (mostly septal defect, one patient had bicuspid aortic valve, aortic aneurysm). Het mouse model had heart defects including truncus arteriosus
Sources: Literature
Congenital Heart Defect v0.279 ACTC1 Zornitza Stark Publications for gene: ACTC1 were set to 17947298; 31430208
Congenital Heart Defect v0.278 ACTC1 Zornitza Stark Classified gene: ACTC1 as Green List (high evidence)
Congenital Heart Defect v0.278 ACTC1 Zornitza Stark Gene: actc1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.277 ACTC1 Lilian Downie reviewed gene: ACTC1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36945405; Phenotypes: Atrial septal defect 5 MIM#612794; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.277 PLXND1 Zornitza Stark Phenotypes for gene: PLXND1 were changed from Congenital heart disease, MONDO:0005453, PLXND1-related to Congenital heart defects, multiple types, 9, MIM# 620294
Congenital Heart Defect v0.276 PLXND1 Zornitza Stark edited their review of gene: PLXND1: Changed phenotypes: Congenital heart defects, multiple types, 9, MIM# 620294
Congenital Heart Defect v0.276 MCF2L Zornitza Stark Marked gene: MCF2L as ready
Congenital Heart Defect v0.276 MCF2L Zornitza Stark Gene: mcf2l has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.276 MCF2L Zornitza Stark Mode of inheritance for gene: MCF2L was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.275 MCF2L Zornitza Stark Classified gene: MCF2L as Red List (low evidence)
Congenital Heart Defect v0.275 MCF2L Zornitza Stark Gene: mcf2l has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.274 PLXND1 Zornitza Stark Marked gene: PLXND1 as ready
Congenital Heart Defect v0.274 PLXND1 Zornitza Stark Gene: plxnd1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.274 PLXND1 Zornitza Stark Classified gene: PLXND1 as Green List (high evidence)
Congenital Heart Defect v0.274 PLXND1 Zornitza Stark Gene: plxnd1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.273 PLXND1 Zornitza Stark gene: PLXND1 was added
gene: PLXND1 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: PLXND1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLXND1 were set to 35396997
Phenotypes for gene: PLXND1 were set to Congenital heart disease, MONDO:0005453, PLXND1-related
Review for gene: PLXND1 was set to GREEN
Added comment: 10 individuals including four fetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT)/truncus arteriosus.
Sources: Literature
Congenital Heart Defect v0.272 MCF2L Michelle Torres gene: MCF2L was added
gene: MCF2L was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: MCF2L was set to Unknown
Publications for gene: MCF2L were set to 36760094
Phenotypes for gene: MCF2L were set to vascular malformation MONDO:0024291, MCF2L-related
Review for gene: MCF2L was set to RED
Added comment: Three families with Systemic malformation (resulting in a left to right shunt instead of the right to left shunt seen in individuals with HHT) had missense variants in the MCF2L gene (families 1, 2 and 7).
Family 1 (Val875Met: v2 & v3: 113 hets) did no present PA (pulmonary artery).
Family 2 (Cys199Gly : v2 & v3: 260 hets, 1 hom) did no present PA (pulmonary artery).
Family 7: Leu130Pro (1 het, 0 hom), segregated in family 7 with SA-PA (systemic artery to the pulmonary artery), with 5x affected tested (Sanger or WES). Unaffected and other 6x individuals affected were not tested.
Sources: Literature
Congenital Heart Defect v0.272 SMPD4 Elena Savva Classified gene: SMPD4 as Green List (high evidence)
Congenital Heart Defect v0.272 SMPD4 Elena Savva Gene: smpd4 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.272 SMPD4 Elena Savva Classified gene: SMPD4 as Green List (high evidence)
Congenital Heart Defect v0.272 SMPD4 Elena Savva Gene: smpd4 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.271 SMPD4 Elena Savva Classified gene: SMPD4 as Green List (high evidence)
Congenital Heart Defect v0.271 SMPD4 Elena Savva Gene: smpd4 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.270 SMPD4 Elena Savva Marked gene: SMPD4 as ready
Congenital Heart Defect v0.270 SMPD4 Elena Savva Gene: smpd4 has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.270 AMOTL1 Seb Lunke Marked gene: AMOTL1 as ready
Congenital Heart Defect v0.270 AMOTL1 Seb Lunke Gene: amotl1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.270 SMPD4 Elena Savva gene: SMPD4 was added
gene: SMPD4 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: SMPD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMPD4 were set to PMID: 36732302
Phenotypes for gene: SMPD4 were set to Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies MIM#618622
Review for gene: SMPD4 was set to GREEN
Added comment: PMID: 36732302 - 44% of patients have a type of congenital heart defect including ASD (16%), persistent ductus arteriosus (20%), long QT (4%), DCM (4%), VSD (8%) and transposition of the great arteries (4%)
Sources: Literature
Congenital Heart Defect v0.270 AMOTL1 Seb Lunke Classified gene: AMOTL1 as Green List (high evidence)
Congenital Heart Defect v0.270 AMOTL1 Seb Lunke Gene: amotl1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.269 AMOTL1 Lucy Spencer gene: AMOTL1 was added
gene: AMOTL1 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: AMOTL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AMOTL1 were set to 36751037
Phenotypes for gene: AMOTL1 were set to Orofacial clefting syndrome, MONDO:0015335, AMOTL1-related
Review for gene: AMOTL1 was set to GREEN
Added comment: PMID: 36751037- 16 individuals from 12 families with orofacial clefting syndrome and het variants in AMOTL1. Many in 1 hotspot: 5 individuals from 3 families have R157C, 6 individuals from another 4 families have R157H, 1 has P160L, and another has Q161R. Out of this hostpaot- 1 with P368A, 1 with E507K, 1 with E579K. 7 are de novo. All but 2 have clefting, 7 are dysmorphic, 5 have hearing loss, 9 have CHD, 7 have tall stature, 6 have dev delay. Other features include liver disease, myopia, scoliosis and immune involvement.

Another 2 families have been previously reported (described in the panelapp review below) with variants in this hotspot 1 has 2 individuals with R157C, the other has 1 individual with P160L. All hotspot are absent from gnomad v2.
Sources: Literature
Congenital Heart Defect v0.269 KDM2B Ain Roesley Classified gene: KDM2B as Green List (high evidence)
Congenital Heart Defect v0.269 KDM2B Ain Roesley Gene: kdm2b has been classified as Green List (High Evidence).
Congenital Heart Defect v0.269 KDM2B Ain Roesley Classified gene: KDM2B as Green List (high evidence)
Congenital Heart Defect v0.269 KDM2B Ain Roesley Gene: kdm2b has been classified as Green List (High Evidence).
Congenital Heart Defect v0.268 KDM2B Ain Roesley Marked gene: KDM2B as ready
Congenital Heart Defect v0.268 KDM2B Ain Roesley Gene: kdm2b has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.268 KDM2B Ain Roesley gene: KDM2B was added
gene: KDM2B was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: KDM2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KDM2B were set to 36322151
Phenotypes for gene: KDM2B were set to neurodevelopmental disorder MONDO#070009, KDM2B-related
Review for gene: KDM2B was set to GREEN
gene: KDM2B was marked as current diagnostic
Added comment: 27 individuals from 22 families were recruited
13 SNV classified LP/P, all de novo except 2 familial cases
5 variants were classified as VUS if more than 1 het is present in gnomAD or does result in a KDM2B-specific episignature (therefore suggesting normal function)

14 families with SNVs and a variety of cardiac anomalies including ASD, VSD, MR, PDA, PFO, Atrial septal aneurysm and Mild mitral insufficiency
Sources: Literature
Congenital Heart Defect v0.267 Zornitza Stark List of related panels changed from to Abnormal heart morphology HP:0001627
Congenital Heart Defect v0.266 ADAMTS19 Zornitza Stark Phenotypes for gene: ADAMTS19 were changed from Non-syndromic heart valve disease to Cardiac valvular dysplasia 2, MIM# 620067
Congenital Heart Defect v0.265 ADAMTS19 Zornitza Stark edited their review of gene: ADAMTS19: Changed phenotypes: Cardiac valvular dysplasia 2, MIM# 620067
Congenital Heart Defect v0.265 DOHH Zornitza Stark Phenotypes for gene: DOHH were changed from Neurodevelopmental disorder, DOHH-related (MONDO#0700092) to Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment, MIM# 620066
Congenital Heart Defect v0.264 DOHH Zornitza Stark reviewed gene: DOHH: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment, MIM# 620066; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.264 NODAL Zornitza Stark Publications for gene: NODAL were set to 9354794; 19064609
Congenital Heart Defect v0.263 NODAL Zornitza Stark Classified gene: NODAL as Amber List (moderate evidence)
Congenital Heart Defect v0.263 NODAL Zornitza Stark Gene: nodal has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.262 NODAL Zornitza Stark edited their review of gene: NODAL: Added comment: NODAL is a good biological candidate for heterotaxy disorders, and this is supported by animal models. The gene is depleted for LoF variants in gnomad.

The missense variants reported in PMIDs 9354794 and 19064609 are present at a high population frequency in gnomad, including some in homozygous case: their association with disease is DISPUTED.

A total of at least 7 families reported with severe CHD and high impact variants (stop gain, frameshift and canonical splice site). However, almost invariably these were inherited from unaffected or questionably affected parents (e.g. self reports of heart murmur in childhood), raising questions about whether these variants contribute to disease under a monogenic or polygenic model and/or about penetrance.

Discussed at GenCC on 13/9/2022 and agreed on MODERATE assessment.; Changed rating: AMBER; Changed publications: 9354794, 19064609, 29368431, 19933292, 11311163, 30293987
Congenital Heart Defect v0.262 ALDH1A2 Zornitza Stark Phenotypes for gene: ALDH1A2 were changed from Congenital heart defects; diaphragmatic eventration; pulmonary hypoplasia; dysmorphic features to Diaphragmatic hernia 4, with cardiovascular defects, MIM# 620025
Congenital Heart Defect v0.261 ALDH1A2 Zornitza Stark reviewed gene: ALDH1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diaphragmatic hernia 4, with cardiovascular defects, MIM# 620025; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.261 ZMYND8 Zornitza Stark Marked gene: ZMYND8 as ready
Congenital Heart Defect v0.261 ZMYND8 Zornitza Stark Gene: zmynd8 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.261 ZMYND8 Zornitza Stark Classified gene: ZMYND8 as Green List (high evidence)
Congenital Heart Defect v0.261 ZMYND8 Zornitza Stark Gene: zmynd8 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.260 ZMYND8 Zornitza Stark gene: ZMYND8 was added
gene: ZMYND8 was added to Congenital Heart Defect. Sources: Expert Review
Mode of inheritance for gene: ZMYND8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZMYND8 were set to 35916866; 32530565
Phenotypes for gene: ZMYND8 were set to Neurodevelopmental disorder, MONDO:0700092, ZMYND8-related; Delayed speech and language development; Motor delay; Intellectual disability; Abnormality of cardiovascular system morphology; Hearing abnormality; Abnormality of vision; Abnormality of the face; Seizures
Review for gene: ZMYND8 was set to GREEN
Added comment: Dias et al (2022 - PMID: 35916866) describe the phenotype of 11 unrelated individuals with monoallelic de novo (or suspected de novo) missense (N=9) or truncating (N=2) ZMYND8 variants. One of these subjects was previously reported by Suzuki et al (2020 - PMID: 32530565).

Features included speech delay/language difficulties (9/11), motor delay (9/11), ID (in 10/11 - profound in 1, moderate in 2), CHD (7/11 - PDA, VSD, ASD, pulmonary stenosis, etc), hearing or vision impairment (7/11). Seizures were reported in few (in text 5/11, table 2/11). Variable non-familial facial features were present in (9/11).

As the authors discuss, ZMYND8 encodes a multidomain protein playing a role in transcription regulation, chromatin remodeling, regulation of super enhancers, DNA damage response/tumor suppression.

The protein is broadly expressed in brain and shows highest expression in early development.

Molecular modeling and/or a yeast two-hybrid system were suggestive of disrupted interaction of ZMYND8 with Drebrin (missense variants in PWWP domain) or GATAD2A (variants in MYND domain).

Neuronal Zmynd8 knockdown in Drosophila resulted in deficits in habituation learning.
Sources: Expert Review
Congenital Heart Defect v0.259 DOHH Zornitza Stark Marked gene: DOHH as ready
Congenital Heart Defect v0.259 DOHH Zornitza Stark Gene: dohh has been classified as Green List (High Evidence).
Congenital Heart Defect v0.259 DOHH Zornitza Stark Classified gene: DOHH as Green List (high evidence)
Congenital Heart Defect v0.259 DOHH Zornitza Stark Gene: dohh has been classified as Green List (High Evidence).
Congenital Heart Defect v0.258 DOHH Daniel Flanagan gene: DOHH was added
gene: DOHH was added to Congenital Heart Defect. Sources: Expert list
Mode of inheritance for gene: DOHH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DOHH were set to PMID: 35858628
Phenotypes for gene: DOHH were set to Neurodevelopmental disorder, DOHH-related (MONDO#0700092)
Review for gene: DOHH was set to GREEN
Added comment: Bi-allelic missense and truncating DOHH variants segregating with disease in five affected individuals from four unrelated families. Clinical features were developmental delay and/or intellectual disability (5/5), microcephaly (5/5), visual impairment (nystagmus (3/5), strabismus (3/5), and cortical visual impairment (1/5)) and congenital heart malformations (3/5 individuals).
Sources: Expert list
Congenital Heart Defect v0.258 DNAH9 Zornitza Stark Marked gene: DNAH9 as ready
Congenital Heart Defect v0.258 DNAH9 Zornitza Stark Gene: dnah9 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.258 DNAH9 Zornitza Stark Classified gene: DNAH9 as Green List (high evidence)
Congenital Heart Defect v0.258 DNAH9 Zornitza Stark Gene: dnah9 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.257 DNAH9 Zornitza Stark gene: DNAH9 was added
gene: DNAH9 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: DNAH9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH9 were set to 35116053; 35050399; 30471717; 30471718
Phenotypes for gene: DNAH9 were set to Ciliary dyskinesia, primary, 40 618300; Heterotaxy
Review for gene: DNAH9 was set to GREEN
Added comment: Multiple families reported including with significant CHD.
Sources: Literature
Congenital Heart Defect v0.256 ROBO4 Zornitza Stark Phenotypes for gene: ROBO4 were changed from bicuspid aortic valve; ascending aortic aneurysm; ascending aorta dilatation to Aortic valve disease 8, MIM# 618496; bicuspid aortic valve; ascending aortic aneurysm; ascending aorta dilatation
Congenital Heart Defect v0.255 ROBO4 Zornitza Stark Classified gene: ROBO4 as Amber List (moderate evidence)
Congenital Heart Defect v0.255 ROBO4 Zornitza Stark Gene: robo4 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.254 ROBO4 Zornitza Stark Deleted their comment
Congenital Heart Defect v0.254 ROBO4 Zornitza Stark edited their review of gene: ROBO4: Added comment: LoF variants in this gene have high frequency in gnomad. Only two families reported. Functional data is not entirely convincing. May be a susceptibility factor to a relatively common phenotype (bicuspid aortic valve).; Changed rating: AMBER; Changed publications: 30455415; Changed phenotypes: Aortic valve disease 8, MIM# 618496, bicuspid aortic valve, ascending aortic aneurysm, ascending aorta dilatation; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.254 KYNU Zornitza Stark Marked gene: KYNU as ready
Congenital Heart Defect v0.254 KYNU Zornitza Stark Gene: kynu has been classified as Green List (High Evidence).
Congenital Heart Defect v0.254 KYNU Zornitza Stark Phenotypes for gene: KYNU were changed from MIM# 617661 Vertebral, cardiac, renal, and limb defects syndrome 2 to Vertebral, cardiac, renal, and limb defects syndrome 2, MIM# 617661
Congenital Heart Defect v0.253 KYNU Zornitza Stark Classified gene: KYNU as Green List (high evidence)
Congenital Heart Defect v0.253 KYNU Zornitza Stark Gene: kynu has been classified as Green List (High Evidence).
Congenital Heart Defect v0.252 KDR Zornitza Stark Marked gene: KDR as ready
Congenital Heart Defect v0.252 KDR Zornitza Stark Gene: kdr has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.252 KDR Zornitza Stark Phenotypes for gene: KDR were changed from Tetralogy of Fallot to Tetralogy of Fallot, MONDO:0008542
Congenital Heart Defect v0.251 KDR Zornitza Stark Mode of inheritance for gene: KDR was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.250 KDR Zornitza Stark Classified gene: KDR as Red List (low evidence)
Congenital Heart Defect v0.250 KDR Zornitza Stark Gene: kdr has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.249 KDR Zornitza Stark reviewed gene: KDR: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Tetralogy of Fallot, MONDO:0008542; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.249 HDAC8 Zornitza Stark Marked gene: HDAC8 as ready
Congenital Heart Defect v0.249 HDAC8 Zornitza Stark Gene: hdac8 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.249 HDAC8 Zornitza Stark Phenotypes for gene: HDAC8 were changed from MIM# 300882 Cornelia de Lange syndrome 5 to Cornelia de Lange syndrome 5, MIM# 300882
Congenital Heart Defect v0.248 HDAC8 Zornitza Stark Mode of inheritance for gene: HDAC8 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Congenital Heart Defect v0.247 HDAC8 Zornitza Stark reviewed gene: HDAC8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cornelia de Lange syndrome 5, MIM# 300882; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Congenital Heart Defect v0.247 HDAC8 Zornitza Stark Classified gene: HDAC8 as Green List (high evidence)
Congenital Heart Defect v0.247 HDAC8 Zornitza Stark Gene: hdac8 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.246 HAAO Zornitza Stark Marked gene: HAAO as ready
Congenital Heart Defect v0.246 HAAO Zornitza Stark Gene: haao has been classified as Green List (High Evidence).
Congenital Heart Defect v0.246 HAAO Zornitza Stark Phenotypes for gene: HAAO were changed from Atrial septal defect; Hypoplastic left heart syndrome; Aortic stenosis; Mitral stenosis; Tetralogy of fallot with complete atriventricular canal and pulmonary stenosis; Lsvc and left pulmonary artery arising from the ductus arteriosus; Shone syndrome with aortic coarctation to Vertebral, cardiac, renal, and limb defects syndrome 1, MIM# 617660; Atrial septal defect; Hypoplastic left heart syndrome; Aortic stenosis; Mitral stenosis; Tetralogy of fallot with complete atriventricular canal and pulmonary stenosis; Lsvc and left pulmonary artery arising from the ductus arteriosus; Shone syndrome with aortic coarctation
Congenital Heart Defect v0.245 HAAO Zornitza Stark Classified gene: HAAO as Green List (high evidence)
Congenital Heart Defect v0.245 HAAO Zornitza Stark Gene: haao has been classified as Green List (High Evidence).
Congenital Heart Defect v0.244 GLI3 Zornitza Stark Marked gene: GLI3 as ready
Congenital Heart Defect v0.244 GLI3 Zornitza Stark Gene: gli3 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.244 GLI3 Zornitza Stark Phenotypes for gene: GLI3 were changed from ASD, VSD, AVSD, aortic arch anomaly, PDA to Pallister-Hall syndrome, MIM# 146510; ASD, VSD, AVSD, aortic arch anomaly, PDA
Congenital Heart Defect v0.243 GLI3 Zornitza Stark Mode of pathogenicity for gene: GLI3 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Other
Congenital Heart Defect v0.242 GLI3 Zornitza Stark Classified gene: GLI3 as Green List (high evidence)
Congenital Heart Defect v0.242 GLI3 Zornitza Stark Gene: gli3 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.241 GLI3 Zornitza Stark reviewed gene: GLI3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pallister-Hall syndrome, MIM# 146510; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.241 FOXP1 Zornitza Stark Marked gene: FOXP1 as ready
Congenital Heart Defect v0.241 FOXP1 Zornitza Stark Gene: foxp1 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.241 FOXP1 Zornitza Stark Phenotypes for gene: FOXP1 were changed from Atrial septal defect; Atrioventricular septal defect; Patent ductus arteriosus; Pulmonic stenosis; Hypoplastic left heart syndrome to Intellectual developmental disorder with language impairment with or without autistic features, MIM# 613670; Atrial septal defect; Atrioventricular septal defect; Patent ductus arteriosus; Pulmonic stenosis; Hypoplastic left heart syndrome
Congenital Heart Defect v0.240 FOXP1 Zornitza Stark Classified gene: FOXP1 as Amber List (moderate evidence)
Congenital Heart Defect v0.240 FOXP1 Zornitza Stark Gene: foxp1 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.239 FOXP1 Zornitza Stark reviewed gene: FOXP1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder with language impairment with or without autistic features, MIM# 613670; Mode of inheritance: None
Congenital Heart Defect v0.239 KYNU Chloe Stutterd gene: KYNU was added
gene: KYNU was added to Congenital Heart Defect. Sources: Literature,Expert list
Mode of inheritance for gene: KYNU was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KYNU were set to 28792876; 33942433
Phenotypes for gene: KYNU were set to MIM# 617661 Vertebral, cardiac, renal, and limb defects syndrome 2
Review for gene: KYNU was set to GREEN
gene: KYNU was marked as current diagnostic
Added comment: Biallelic, inactivating variants in three genes encoding enzymes of the NAD biosynthesis pathway (KYNU, HAAO, and NADSYN1) disrupt NAD synthesis and have been identified in patients with multiple malformations of the heart, kidney, vertebrae, and limbs; these patients have Congenital NAD Deficiency Disorder (PMID: 33942433)
Sources: Literature, Expert list
Congenital Heart Defect v0.239 KDR Chloe Stutterd gene: KDR was added
gene: KDR was added to Congenital Heart Defect. Sources: Literature,Expert list
Mode of inheritance for gene: KDR was set to Unknown
Publications for gene: KDR were set to 34113005; 34328347; 30232381
Phenotypes for gene: KDR were set to Tetralogy of Fallot
Review for gene: KDR was set to RED
gene: KDR was marked as current diagnostic
Added comment: Rare variants associated with ToF but lacking evidence for causality and pathogenesis.

PMID 34113005 (2021): Exome sequencing in a family with two siblings affected by TOF revealed biallelic missense variants in KDR. Studies in knock-in mice and in HEK 293T cells identified embryonic lethality for one variant when occurring in the homozygous state, and a significantly reduced VEGFR2 phosphorylation for both variants. Rare variant burden analysis conducted in a set of 1,569 patients of European descent with TOF identified a 46-fold enrichment of protein-truncating variants (PTVs) in TOF cases compared to controls (P = 7 × 10-11).

PMID 34328347 (2021): exome sequencing data from 811 probands with ToF, four patients had novel LoF variants in KDR demonstrating enrichment in ToF compared with controls. Segregation data not available.

PMID: 30232381 (2019): KDR variants identified in four patients (two stopgain and two nonsynonymous variants) with other VUS identified in one patient. Segregation data not available.
Sources: Literature, Expert list
Congenital Heart Defect v0.239 HDAC8 Chloe Stutterd gene: HDAC8 was added
gene: HDAC8 was added to Congenital Heart Defect. Sources: Literature,Expert list
Mode of inheritance for gene: HDAC8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HDAC8 were set to 24403048
Phenotypes for gene: HDAC8 were set to MIM# 300882 Cornelia de Lange syndrome 5
Review for gene: HDAC8 was set to GREEN
gene: HDAC8 was marked as current diagnostic
Added comment: PMID:24403048: 11/30 individuals with HDAC8-related CdLS identified with CHD (ASD, VSD, ToF, valve dysplasia, PDA)(Supp table).
Sources: Literature, Expert list
Congenital Heart Defect v0.239 HAAO Chloe Stutterd edited their review of gene: HAAO: Added comment: CHD reported: Atrial septal defect; Hypoplastic left heart syndrome; Aortic stenosis; Mitral stenosis; Tetralogy of fallot with complete atriventricular canal and pulmonary stenosis; Lsvc and left pulmonary artery arising from the ductus arteriosus; Shone syndrome with aortic coarctation; Changed phenotypes: MIM#617660 Vertebral, cardiac, renal, and limb defects syndrome 1
Congenital Heart Defect v0.239 HAAO Chloe Stutterd gene: HAAO was added
gene: HAAO was added to Congenital Heart Defect. Sources: Literature,Expert list
Mode of inheritance for gene: HAAO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HAAO were set to 28792876; 33942433
Phenotypes for gene: HAAO were set to Atrial septal defect; Hypoplastic left heart syndrome; Aortic stenosis; Mitral stenosis; Tetralogy of fallot with complete atriventricular canal and pulmonary stenosis; Lsvc and left pulmonary artery arising from the ductus arteriosus; Shone syndrome with aortic coarctation
Review for gene: HAAO was set to GREEN
gene: HAAO was marked as current diagnostic
Added comment: MIM#617660 phenotype is called 'Vertebral, cardiac, renal, and limb defects syndrome type 1' and is a form of Congenital NAD Deficiency Disorder.

Biallelic, inactivating variants in three genes encoding enzymes of the NAD biosynthesis pathway (KYNU, HAAO, and NADSYN1) disrupt NAD synthesis and have been identified in patients with multiple malformations of the heart, kidney, vertebrae, and limbs; these patients have Congenital NAD Deficiency Disorder (PMID: 33942433).
Sources: Literature, Expert list
Congenital Heart Defect v0.239 GLI3 Chloe Stutterd gene: GLI3 was added
gene: GLI3 was added to Congenital Heart Defect. Sources: Literature,Expert list
Mode of inheritance for gene: GLI3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GLI3 were set to 24736735; 7211952
Phenotypes for gene: GLI3 were set to ASD, VSD, AVSD, aortic arch anomaly, PDA
Mode of pathogenicity for gene: GLI3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: GLI3 was set to GREEN
gene: GLI3 was marked as current diagnostic
Added comment: Syndromic CHD associated with the Pallister-Hall syndrome (PHS) phenotype which is caused by truncating mutations in the middle third of the gene that produce a truncated functional repressor protein.

OMIM #146510 (Pallister-Hall syndrome; PHS) phenotype includes ventricular septal defect, aortic coarctation and patent ductus arteriosus based on original clinical description of syndrome in 1980 in patients without molecular confirmation of diagnosis (PubMed 7211952)

PMID 24736735 (2015): French cohort of 76 individuals from 55 families carrying a GLI3 molecular defect. CHD identified in 5/21 unrelated patients with PHS (septal defects, aortic arch anomaly).
Sources: Literature, Expert list
Congenital Heart Defect v0.239 FOXP1 Chloe Stutterd gene: FOXP1 was added
gene: FOXP1 was added to Congenital Heart Defect. Sources: Literature,Expert list
Mode of inheritance for gene: FOXP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXP1 were set to 29090079; 23766104
Phenotypes for gene: FOXP1 were set to Atrial septal defect; Atrioventricular septal defect; Patent ductus arteriosus; Pulmonic stenosis; Hypoplastic left heart syndrome
Review for gene: FOXP1 was set to AMBER
gene: FOXP1 was marked as current diagnostic
Added comment: Best evidence of association with CHD comes from PMID:29090079 but only for two patients and one with very mild CHD only. Study is a prospective investigation of nine children with FOXP1 syndrome using a battery of standardized clinical assessments, two had CHD (one with pulmonary stenosis, the other with self-resolving PDA). Authors recommend cardiac screening for patients with FOXP1 neurodevelopmental syndrome.

PMID:23766104: Single patient with CHD (AVSD, hypoplastic left ventricle and aortic arch, left atrioventricular valve stenosis, bilateral superior vena cavae, transposed great vessels) and cryptorchidism and a novel 3p14 microdeletion involving first 4 exons of FOXP1, inherited from an unaffected mother. FOXP1 sequenced in 82 patients with AVSD or HLHS: 2/82 patients had FOXP1 variant c.1702C>T;p.(Pro568Ser), inheritance unknown, variant present gnomAD in 153 hets, benign/likely benign in ClinVar .

PMID: 25908055; 22290856: CHD associated with 3p14 contiguous gene deletion syndrome involving FOXP1 and up to 30 other genes.

Homozygous null mice have CHD (MGI ID:1914004; PMID: 15342473).
Sources: Literature, Expert list
Congenital Heart Defect v0.239 ANKRD11 Zornitza Stark Marked gene: ANKRD11 as ready
Congenital Heart Defect v0.239 ANKRD11 Zornitza Stark Gene: ankrd11 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.239 ANKRD11 Zornitza Stark Phenotypes for gene: ANKRD11 were changed from to KBG syndrome, MIM# 148050
Congenital Heart Defect v0.238 ANKRD11 Zornitza Stark Publications for gene: ANKRD11 were set to
Congenital Heart Defect v0.237 ANKRD11 Zornitza Stark Mode of inheritance for gene: ANKRD11 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.236 ANKRD11 Zornitza Stark reviewed gene: ANKRD11: Rating: GREEN; Mode of pathogenicity: None; Publications: 27605097; Phenotypes: KBG syndrome 148050; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.236 ADAMTS10 Zornitza Stark Marked gene: ADAMTS10 as ready
Congenital Heart Defect v0.236 ADAMTS10 Zornitza Stark Gene: adamts10 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.236 ADAMTS10 Zornitza Stark Phenotypes for gene: ADAMTS10 were changed from to Weill-Marchesani syndrome 1, recessive, MIM# 277600
Congenital Heart Defect v0.235 ADAMTS10 Zornitza Stark Publications for gene: ADAMTS10 were set to
Congenital Heart Defect v0.234 ADAMTS10 Zornitza Stark Mode of inheritance for gene: ADAMTS10 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.233 ADAMTS10 Zornitza Stark reviewed gene: ADAMTS10: Rating: GREEN; Mode of pathogenicity: None; Publications: 15368195, 18567016, 19836009; Phenotypes: Weill-Marchesani syndrome 1, recessive, MIM# 277600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.233 ACVR1 Zornitza Stark Marked gene: ACVR1 as ready
Congenital Heart Defect v0.233 ACVR1 Zornitza Stark Gene: acvr1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.233 ACVR1 Zornitza Stark Phenotypes for gene: ACVR1 were changed from to Congenital heart disease, MONDO:0005453
Congenital Heart Defect v0.232 ACVR1 Zornitza Stark Publications for gene: ACVR1 were set to
Congenital Heart Defect v0.231 ACVR1 Zornitza Stark Mode of inheritance for gene: ACVR1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.230 ACVR1 Zornitza Stark reviewed gene: ACVR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29089047, 19506109, 21248739; Phenotypes: Congenital heart disease, MONDO:0005453; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.230 ESCO2 Zornitza Stark Marked gene: ESCO2 as ready
Congenital Heart Defect v0.230 ESCO2 Zornitza Stark Gene: esco2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.230 ESCO2 Zornitza Stark Phenotypes for gene: ESCO2 were changed from Atrial septal defect; Ventricular septal defect; Pulmonic stenosis; tricuspid regurgitation to Roberts-SC phocomelia syndrome, MIM# 268300; Atrial septal defect; Ventricular septal defect; Pulmonic stenosis; tricuspid regurgitation
Congenital Heart Defect v0.229 ESCO2 Zornitza Stark Classified gene: ESCO2 as Green List (high evidence)
Congenital Heart Defect v0.229 ESCO2 Zornitza Stark Gene: esco2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.228 EP300 Zornitza Stark Marked gene: EP300 as ready
Congenital Heart Defect v0.228 EP300 Zornitza Stark Gene: ep300 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.228 EP300 Zornitza Stark Marked gene: EP300 as ready
Congenital Heart Defect v0.228 EP300 Zornitza Stark Gene: ep300 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.228 EP300 Zornitza Stark Phenotypes for gene: EP300 were changed from Ventricular septal defect; Patent foramen ovale; Patent ductus arteriosus; mild valve dysplasia to Rubinstein-Taybi syndrome 2, MIM# 613684
Congenital Heart Defect v0.227 EP300 Zornitza Stark Classified gene: EP300 as Green List (high evidence)
Congenital Heart Defect v0.227 EP300 Zornitza Stark Gene: ep300 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.226 EP300 Zornitza Stark reviewed gene: EP300: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Rubinstein-Taybi syndrome 2, MIM# 613684; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.226 DNAH5 Zornitza Stark Marked gene: DNAH5 as ready
Congenital Heart Defect v0.226 DNAH5 Zornitza Stark Gene: dnah5 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.226 DNAH5 Zornitza Stark Phenotypes for gene: DNAH5 were changed from Atrial septal defect; Ventricular septal defect; Atrioventricular septal defect; Transposition of the great arteries to Ciliary dyskinesia, primary, 3, with or without situs inversus, MIM# 608644
Congenital Heart Defect v0.225 DNAH5 Zornitza Stark Classified gene: DNAH5 as Green List (high evidence)
Congenital Heart Defect v0.225 DNAH5 Zornitza Stark Gene: dnah5 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.224 DNAH5 Zornitza Stark reviewed gene: DNAH5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 3, with or without situs inversus, MIM# 608644; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.224 CHST14 Zornitza Stark Marked gene: CHST14 as ready
Congenital Heart Defect v0.224 CHST14 Zornitza Stark Gene: chst14 has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.224 CHST14 Zornitza Stark Phenotypes for gene: CHST14 were changed from Atrial septal defect; Coarctation of the aorta to Ehlers-Danlos syndrome, musculocontractural type 1, MIM# 601776
Congenital Heart Defect v0.223 CHST14 Zornitza Stark Classified gene: CHST14 as Red List (low evidence)
Congenital Heart Defect v0.223 CHST14 Zornitza Stark Gene: chst14 has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.222 CHST14 Zornitza Stark reviewed gene: CHST14: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ehlers-Danlos syndrome, musculocontractural type 1, MIM# 601776; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.222 CFC1 Zornitza Stark Marked gene: CFC1 as ready
Congenital Heart Defect v0.222 CFC1 Zornitza Stark Gene: cfc1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.222 CFC1 Zornitza Stark Phenotypes for gene: CFC1 were changed from Atrioventricular septal defect; Interrupted aortic arch; Tetralogy of fallot; Transposition of the great arteries; Truncus arteriosus; Double outlet right ventricle; Heterotaxy to Heterotaxy, visceral, 2, MIM# 605376
Congenital Heart Defect v0.221 CFC1 Zornitza Stark Publications for gene: CFC1 were set to
Congenital Heart Defect v0.220 CFC1 Zornitza Stark Classified gene: CFC1 as Green List (high evidence)
Congenital Heart Defect v0.220 CFC1 Zornitza Stark Gene: cfc1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.219 CFC1 Zornitza Stark reviewed gene: CFC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31633655, 18162845, 25423076, 11062482; Phenotypes: Heterotaxy, visceral, 2, MIM# 605376; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.219 ESCO2 Chloe Stutterd gene: ESCO2 was added
gene: ESCO2 was added to Congenital Heart Defect. Sources: Expert list,Literature
Mode of inheritance for gene: ESCO2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ESCO2 were set to 19574259; 31976146
Phenotypes for gene: ESCO2 were set to Atrial septal defect; Ventricular septal defect; Pulmonic stenosis; tricuspid regurgitation
Penetrance for gene: ESCO2 were set to Complete
Review for gene: ESCO2 was set to GREEN
gene: ESCO2 was marked as current diagnostic
Added comment: CHD reported in 8/31 patients with molecularly-confirmed Roberts syndrome (PMID 19574259). Septal defect and tricuspid regurgitation reported in one patient with molecularly-confirmed Roberts syndrome (PMID:31976146).
Sources: Expert list, Literature
Congenital Heart Defect v0.219 EP300 Chloe Stutterd gene: EP300 was added
gene: EP300 was added to Congenital Heart Defect. Sources: Expert list,Literature
Mode of inheritance for gene: EP300 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EP300 were set to 24352918; 24476420
Phenotypes for gene: EP300 were set to Ventricular septal defect; Patent foramen ovale; Patent ductus arteriosus; mild valve dysplasia
Penetrance for gene: EP300 were set to unknown
Review for gene: EP300 was set to AMBER
gene: EP300 was marked as current diagnostic
Added comment: Included in Victor Chang CHD gene list. Mice homozygotes for targeted null mutations have CHD (MGI ID: 1276116). Five patients reported with with CHD (VSD, PFO, PDA, valve dysplasia), all with extra-cardiac features of Rubinstein–Taybi syndrome (24352918; 24476420).
Sources: Expert list, Literature
Congenital Heart Defect v0.219 DNAH5 Chloe Stutterd gene: DNAH5 was added
gene: DNAH5 was added to Congenital Heart Defect. Sources: Expert list,Literature
Mode of inheritance for gene: DNAH5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH5 were set to 31638833
Phenotypes for gene: DNAH5 were set to Atrial septal defect; Ventricular septal defect; Atrioventricular septal defect; Transposition of the great arteries
Penetrance for gene: DNAH5 were set to unknown
Review for gene: DNAH5 was set to AMBER
gene: DNAH5 was marked as current diagnostic
Added comment: Gene included in Victor Chang CHD gene list but all references to CHD are in association with heterotaxy. PMID 31638833: 8/132 (6.1%) patients with DNAH5-associated primary ciliary dyskinesia presented with CHD (septal defects with or without valve and vessel defects) and all had heterotaxy (three with situs solitus and five had situs inversus).
Sources: Expert list, Literature
Congenital Heart Defect v0.219 CHST14 Chloe Stutterd gene: CHST14 was added
gene: CHST14 was added to Congenital Heart Defect. Sources: Expert list,Literature
Mode of inheritance for gene: CHST14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHST14 were set to 20503305
Phenotypes for gene: CHST14 were set to Atrial septal defect; Coarctation of the aorta
Penetrance for gene: CHST14 were set to unknown
Review for gene: CHST14 was set to RED
Added comment: Gene included in Victor Chang CHD gene list however evidence does not exist for causality of significant or isolated CHD and only reported in association with the EDS phenotype. PMID 20503305 reports one patient with EDS and moderate tricuspid valve regurgitation, prolapse of the tricuspid and mitral valves, and left-to-right shunt via a small atrial septal defect, and two patients with valvular regurgitation diagnosed in adulthood in association with the EDS phenotype.
Sources: Expert list, Literature
Congenital Heart Defect v0.219 CFC1 Chloe Stutterd gene: CFC1 was added
gene: CFC1 was added to Congenital Heart Defect. Sources: Expert list,Literature
Mode of inheritance for gene: CFC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CFC1 were set to Atrioventricular septal defect; Interrupted aortic arch; Tetralogy of fallot; Transposition of the great arteries; Truncus arteriosus; Double outlet right ventricle; Heterotaxy
Penetrance for gene: CFC1 were set to unknown
Review for gene: CFC1 was set to RED
Added comment: Strong evidence for causality of heterotaxy syndromes with congenital cardiac malformations (11062482), however investigation of CFC1 as a cause of isolated CHD identified only the polymorphism R78W or the A145T variant which was also present in controls (11799476; 17072672).
Sources: Expert list, Literature
Congenital Heart Defect v0.219 AFF4 Zornitza Stark Marked gene: AFF4 as ready
Congenital Heart Defect v0.219 AFF4 Zornitza Stark Gene: aff4 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.219 AFF4 Zornitza Stark Phenotypes for gene: AFF4 were changed from ventricular septal defect; patent ductus arteriosus; patent foramen ovale to CHOPS syndrome, MIM# 616368; ventricular septal defect; patent ductus arteriosus; patent foramen ovale
Congenital Heart Defect v0.218 AFF4 Zornitza Stark Classified gene: AFF4 as Green List (high evidence)
Congenital Heart Defect v0.218 AFF4 Zornitza Stark Gene: aff4 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.217 ACTC1 Zornitza Stark commented on gene: ACTC1: E101K is multiply reported as pathogenic/likely pathogenic for HCM rather than CHD in ClinVar.

The 17bp deletion was inherited from a parent, with a very questionable affected status (posteriorly deviated interventricular septum).
Congenital Heart Defect v0.217 AFF4 Chloe Stutterd gene: AFF4 was added
gene: AFF4 was added to Congenital Heart Defect. Sources: Literature,Expert Review
Mode of inheritance for gene: AFF4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AFF4 were set to 25730767; 31058441
Phenotypes for gene: AFF4 were set to ventricular septal defect; patent ductus arteriosus; patent foramen ovale
Review for gene: AFF4 was set to GREEN
Added comment: At least 15 unrelated individuals reported. CdL-like, clinically recognisable phenotype, characterised by cognitive impairment, coarse facies, heart defects, obesity, pulmonary involvement, short stature, and skeletal dysplasia. CHD include VSD, PDA, PFO.
Sources: Literature, Expert Review
Congenital Heart Defect v0.217 ACTC1 Chloe Stutterd reviewed gene: ACTC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17611253, 17947298; Phenotypes: Atrial septal defect, Ventricular septal defect; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Congenital Heart Defect v0.217 PAN2 Zornitza Stark Marked gene: PAN2 as ready
Congenital Heart Defect v0.217 PAN2 Zornitza Stark Gene: pan2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.217 PAN2 Seb Lunke Classified gene: PAN2 as Green List (high evidence)
Congenital Heart Defect v0.217 PAN2 Seb Lunke Gene: pan2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.216 PAN2 Seb Lunke Classified gene: PAN2 as Green List (high evidence)
Congenital Heart Defect v0.216 PAN2 Seb Lunke Gene: pan2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.216 PAN2 Seb Lunke Classified gene: PAN2 as Green List (high evidence)
Congenital Heart Defect v0.216 PAN2 Seb Lunke Gene: pan2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.215 PAN2 Naomi Baker gene: PAN2 was added
gene: PAN2 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: PAN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAN2 were set to PMID:35304602; 29620724
Phenotypes for gene: PAN2 were set to Syndromic disease MONDO:0002254
Review for gene: PAN2 was set to GREEN
Added comment: PMID:35304602 reports five individuals from 3 families with biallelic (homozygous) loss-of-function variants. Clinical presentation incudes mild-moderate intellectual disability, hypotonia, sensorineural hearing loss, EEG abnormalities, congenital heart defects (tetralogy of Fallot, septal defects, dilated aortic root), urinary tract malformations, ophthalmological anomalies, short stature with other skeletal anomalies, and craniofacial features including flat occiput, ptosis, long philtrum, and short neck.

PMID:29620724 reports one individual with biallelic (homozygous) loss-of-function variant who presented with global developmental delay, mild hypotonia, craniosynostosis, severe early-onset scoliosis, imperforate anus, and double urinary collecting system.
Sources: Literature
Congenital Heart Defect v0.215 RBFOX2 Zornitza Stark Marked gene: RBFOX2 as ready
Congenital Heart Defect v0.215 RBFOX2 Zornitza Stark Gene: rbfox2 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.215 RBFOX2 Zornitza Stark Classified gene: RBFOX2 as Amber List (moderate evidence)
Congenital Heart Defect v0.215 RBFOX2 Zornitza Stark Gene: rbfox2 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.214 RBFOX2 Zornitza Stark gene: RBFOX2 was added
gene: RBFOX2 was added to Congenital Heart Defect. Sources: Expert Review
Mode of inheritance for gene: RBFOX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RBFOX2 were set to 26785492; 27670201; 27485310; 25205790; 35137168; 26785492
Phenotypes for gene: RBFOX2 were set to Hypoplastic left heart syndrome (HLHS) MONDO:0004933
Review for gene: RBFOX2 was set to AMBER
Added comment: - PMID: 26785492: Analysed CHD (1213 congenital heart disease trios) and control (autism spectrum disorder) trios for de novo mutations. Found RBFOX2 gene had significantly more damaging de novo variants than expected: 3 de novo LoF variants (eg. nonsense, frameshift, or canonical splice disruptions). All 3 probands have hypoplastic left heart syndrome (HLHS). No further patient-specific clinical or variant info were available. Same cohort later included in PMID: 32368696, listed 4 de novo variants in this gene, in patients with left ventricular outflow tract obstruction (LVOTO) or conotruncal defects (CTDs).

- PMID: 27670201: RNA expression study showed the silenced allele harbours a nonsense RBFOX2 variant (Arg287*), CHD patient heart tissue sample, same patient published in PMID: 26785492.
- PMID: 27485310: Functional studies using heart tissue sample from HLHS patient with NM_001031695.2:c.859C>T p.(Arg287*) showed subcellular mislocalisation, impacting its nuclear function in RNA splicing.

- PMID: 25205790: De novo 111.3kb del chr22:36038076-36149338 (hg19) which includes APOL5,APOL6,RBFOX2, in a patient with HLHS.

- PMID: 35137168: Rbfox2 conditional knockout mouse model recapitulated several molecular and phenotypic features of HLHS.
Sources: Expert Review
Congenital Heart Defect v0.213 MAPKAPK5 Zornitza Stark Phenotypes for gene: MAPKAPK5 were changed from Developmental delay, variable brain anomalies, congenital heart defects, dysmorphic to Neurocardiofaciodigital syndrome, MIM# 619869
Congenital Heart Defect v0.212 MAPKAPK5 Zornitza Stark edited their review of gene: MAPKAPK5: Changed phenotypes: Neurocardiofaciodigital syndrome, MIM# 619869
Congenital Heart Defect v0.212 NR2F2 Krithika Murali reviewed gene: NR2F2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24702954, 29478779, 31687637, 27363585, 29222010, 29663647; Phenotypes: 46,XX sex reversal 5 - MIM#618901, Congenital heart defects, multiple types, 4 - MIM#615779; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.212 SON Zornitza Stark Marked gene: SON as ready
Congenital Heart Defect v0.212 SON Zornitza Stark Gene: son has been classified as Green List (High Evidence).
Congenital Heart Defect v0.212 SON Zornitza Stark Phenotypes for gene: SON were changed from to ZTTK syndrome, MIM# 617140
Congenital Heart Defect v0.211 SON Zornitza Stark Publications for gene: SON were set to
Congenital Heart Defect v0.210 SON Zornitza Stark Mode of inheritance for gene: SON was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.209 SON Zornitza Stark reviewed gene: SON: Rating: GREEN; Mode of pathogenicity: None; Publications: 27545680, 27545676, 31005274; Phenotypes: ZTTK syndrome, MIM# 617140; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.209 TFAP2B Zornitza Stark Marked gene: TFAP2B as ready
Congenital Heart Defect v0.209 TFAP2B Zornitza Stark Gene: tfap2b has been classified as Green List (High Evidence).
Congenital Heart Defect v0.209 TFAP2B Zornitza Stark Phenotypes for gene: TFAP2B were changed from to Char syndrome, MIM# 169100; Patent ductus arteriosus 2, MIM# 617035
Congenital Heart Defect v0.208 TFAP2B Zornitza Stark Publications for gene: TFAP2B were set to
Congenital Heart Defect v0.207 TFAP2B Zornitza Stark Mode of inheritance for gene: TFAP2B was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.206 TFAP2B Zornitza Stark reviewed gene: TFAP2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 11505339, 15684060, 18752453, 21643846; Phenotypes: Char syndrome, MIM# 169100, Patent ductus arteriosus 2, MIM# 617035; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.206 NOTCH2 Zornitza Stark Marked gene: NOTCH2 as ready
Congenital Heart Defect v0.206 NOTCH2 Zornitza Stark Gene: notch2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.206 NOTCH2 Zornitza Stark Phenotypes for gene: NOTCH2 were changed from to Alagille syndrome 2 (MIM#610205); Hajdu-Cheney syndrome (MIM#102500)
Congenital Heart Defect v0.205 NOTCH2 Zornitza Stark Publications for gene: NOTCH2 were set to
Congenital Heart Defect v0.204 NOTCH2 Zornitza Stark Mode of inheritance for gene: NOTCH2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.203 NOTCH1 Zornitza Stark Marked gene: NOTCH1 as ready
Congenital Heart Defect v0.203 NOTCH1 Zornitza Stark Gene: notch1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.203 NOTCH1 Zornitza Stark Phenotypes for gene: NOTCH1 were changed from to Adams-Oliver syndrome 5 (MIM#616028)
Congenital Heart Defect v0.202 NOTCH1 Zornitza Stark Publications for gene: NOTCH1 were set to
Congenital Heart Defect v0.201 NOTCH1 Zornitza Stark Mode of inheritance for gene: NOTCH1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.200 NOTCH2 Krithika Murali reviewed gene: NOTCH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 16773578, 21378985, 21378989; Phenotypes: Alagille syndrome 2 (MIM#610205), Hajdu-Cheney syndrome (MIM#102500); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.200 NOTCH1 Krithika Murali reviewed gene: NOTCH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25963545, 25132448; Phenotypes: Adams-Oliver syndrome 5 (MIM#616028); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.200 NAA15 Zornitza Stark Marked gene: NAA15 as ready
Congenital Heart Defect v0.200 NAA15 Zornitza Stark Gene: naa15 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.200 NAA15 Zornitza Stark Classified gene: NAA15 as Green List (high evidence)
Congenital Heart Defect v0.200 NAA15 Zornitza Stark Gene: naa15 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.199 NAA15 Krithika Murali Deleted their comment
Congenital Heart Defect v0.199 NAA15 Krithika Murali edited their review of gene: NAA15: Added comment: Monoallelic variants associated with syndromic ID. At least 47 individuals from 42 unrelated families in the published literature. Phenotypic features reported include:

- ID (all)
- Mild dysmorphic features (20/30)
- ASD/ADHD/behavioural issues (30/33)
- Skeletal and connective tissue anomalies (10/22)
- Congenital heart defects (4/19)
- Hypertrophic cardiomyopathy (paediatric onset) - 2 unrelated individuals (PMID: 33103328)

In addition:

PMID 33557580 - WES of 4511 patients with CHD identified 4 subjects with a rare LoF variant (allele frequency <0.00005) in the NAA15 gene, resulting in NAA15 haploinsufficiency. Parental analyses indicated that 3 of these LoF variants (p.Ser761*, p.Lys336Lys fs*6, and p.Arg470*) arose de novo in the probands. The inheritance of the p.Ala718fs variant is uncertain, as parental samples were unavailable. The authors also reference their previous studies identifying 2 other patients with CHD and LoF NAA15 heterozygous variants.; Changed phenotypes: Intellectual developmental disorder, autosomal dominant 50, with behavioral abnormalities - MIM#617787, congenital heart defect
Congenital Heart Defect v0.199 NAA15 Krithika Murali gene: NAA15 was added
gene: NAA15 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: NAA15 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NAA15 were set to 33103328; 29656860; 31127942; 28191889; 33557580; 28990276
Phenotypes for gene: NAA15 were set to Intellectual developmental disorder, autosomal dominant 50, with behavioral abnormalities - MIM#617787
Review for gene: NAA15 was set to GREEN
Added comment: Monoallelic variants associated with syndromic ID. At least 47 individuals from 42 unrelated families in the published literature. Phenotypic features reported include:

- ID (all)
- Mild dysmorphic features (20/30)
- ASD/ADHD/behavioural issues (30/33)
- Skeletal and connective tissue anomalies (10/22)
- Congenital heart defects (4/19)
- Hypertrophic cardiomyopathy (paediatric onset) - 2 unrelated individuals (PMID: 33103328)

In addition:

PMID 33557580 - WES of 4511 patients with CHD identified 4 subjects with a rare LoF variant (allele frequency <0.00005) in the NAA15 gene, resulting in NAA15 haploinsufficiency. Parental analyses indicated that 3 of these LoF variants (p.Ser761*, p.Lys336Lys fs*6, and p.Arg470*) arose de novo in the probands. The inheritance of the p.Ala718fs variant is uncertain, as parental samples were unavailable. The authors also reference their previous studies identifying 2 other patients with CHD and LoF NAA15 heterozygous variants.
Sources: Literature
Congenital Heart Defect v0.199 ZFPM2 Zornitza Stark Marked gene: ZFPM2 as ready
Congenital Heart Defect v0.199 ZFPM2 Zornitza Stark Gene: zfpm2 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.199 ZFPM2 Zornitza Stark Phenotypes for gene: ZFPM2 were changed from to Tetralogy of Fallot, MIM# 187500
Congenital Heart Defect v0.198 ZFPM2 Zornitza Stark Publications for gene: ZFPM2 were set to
Congenital Heart Defect v0.197 ZFPM2 Zornitza Stark Mode of inheritance for gene: ZFPM2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.196 ZFPM2 Zornitza Stark Classified gene: ZFPM2 as Amber List (moderate evidence)
Congenital Heart Defect v0.196 ZFPM2 Zornitza Stark Gene: zfpm2 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.195 ZFPM2 Zornitza Stark reviewed gene: ZFPM2: Rating: AMBER; Mode of pathogenicity: None; Publications: 21919901, 24469719, 26959486; Phenotypes: Tetralogy of Fallot, MIM# 187500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.195 AL117258.1 Zornitza Stark Phenotypes for gene: AL117258.1 were changed from Heterotaxy, MONDO:0018677; congenital heart defects to Heterotaxy, MONDO:0018677; congenital heart defects
Congenital Heart Defect v0.194 AL117258.1 Zornitza Stark Marked gene: AL117258.1 as ready
Congenital Heart Defect v0.194 AL117258.1 Zornitza Stark Gene: al117258.1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.194 AL117258.1 Zornitza Stark Phenotypes for gene: AL117258.1 were changed from Heterotaxy; congenital heart defects to Heterotaxy, MONDO:0018677; congenital heart defects
Congenital Heart Defect v0.193 AL117258.1 Zornitza Stark Classified gene: AL117258.1 as Green List (high evidence)
Congenital Heart Defect v0.193 AL117258.1 Zornitza Stark Gene: al117258.1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.192 AL117258.1 Melanie Marty gene: AL117258.1 was added
gene: AL117258.1 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: AL117258.1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AL117258.1 were set to 34903892
Phenotypes for gene: AL117258.1 were set to Heterotaxy; congenital heart defects
Review for gene: AL117258.1 was set to GREEN
Added comment: Gene also known as CIROP and LMLN2

Homozygous or compound heterozygous CIROP variants identified in 12 families with congenital heart defects associated with heterotaxy.

Functional tests performed on Xenopus and zebrafish embryos showed that CIROP was essential for left side symmetry and is expressed in ciliated left–right organisers.
Sources: Literature
Congenital Heart Defect v0.192 MAPK1 Zornitza Stark Marked gene: MAPK1 as ready
Congenital Heart Defect v0.192 MAPK1 Zornitza Stark Gene: mapk1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.192 MAPK1 Zornitza Stark Classified gene: MAPK1 as Green List (high evidence)
Congenital Heart Defect v0.192 MAPK1 Zornitza Stark Gene: mapk1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.191 MAPK1 Krithika Murali gene: MAPK1 was added
gene: MAPK1 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: MAPK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAPK1 were set to 32721402
Phenotypes for gene: MAPK1 were set to Noonan syndrome 13 - MIM#619087
Review for gene: MAPK1 was set to GREEN
Added comment: Associated with Noonan syndrome including congenital heart defects. No new publications since last PanelApp review Aug 2020

--
Motta et al (2020 - PMID: 32721402) report on 7 unrelated individuals harboring de novo missense MAPK1 pathogenic variants.

The phenotype corresponded to a neurodevelopmental disorder and - as the authors comment - consistently included DD, ID , behavioral problems. Postnatal growth delay was observed in approximately half. Hypertelorism, ptosis, downslant of palpebral fissures, wide nasal bridge as low-set/posteriorly rotated ears were among the facial features observed (each in 3 or more subjects within this cohort). Together with short/webbed neck and abnormalities of skin (lentigines / CAL spots) and growth delay these led to clinical suspicion of Noonan s. or disorder of the same pathway in some. Congenital heart defects (ASD, mitral valve insufficiency, though not cardiomyopathy) occurred in 4/7. Bleeding diathesis and lymphedema were reported only once.

MAPK1 encodes the mitogen-activated protein kinase 1 (also known as ERK2) a serine/threonine kinase of the RAS-RAF-MEK-(MAPK/)ERK pathway.

MAPK1 de novo variants were identified in all individuals following trio exome sequencing (and extensive previous genetic investigations which were non-diagnostic).

The distribution of variants, as well as in silico/vitro/vivo studies suggest a GoF effect (boosted signal through the MAPK cascade. MAPK signaling also upregulated in Noonan syndrome).
Sources: Literature
Congenital Heart Defect v0.191 SEMA3A Zornitza Stark Marked gene: SEMA3A as ready
Congenital Heart Defect v0.191 SEMA3A Zornitza Stark Gene: sema3a has been classified as Green List (High Evidence).
Congenital Heart Defect v0.191 SEMA3A Zornitza Stark Mode of inheritance for gene: SEMA3A was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.190 SEMA3A Zornitza Stark Classified gene: SEMA3A as Green List (high evidence)
Congenital Heart Defect v0.190 SEMA3A Zornitza Stark Gene: sema3a has been classified as Green List (High Evidence).
Congenital Heart Defect v0.189 SEMA3A Krithika Murali gene: SEMA3A was added
gene: SEMA3A was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: SEMA3A was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: SEMA3A were set to 28075028; 33369061; 20301509; 21059704; 24124006; 22927827
Phenotypes for gene: SEMA3A were set to {Hypogonadotropic hypogonadism 16 with or without anosmia - MIM#614897; congenital heart disease; short stature
Review for gene: SEMA3A was set to GREEN
Added comment: Heterozygous variants associated with isolated GnRH deficiency with or without anosmia (Kallman syndrome like). More severe phenotype with biallelic SEMA3A variants including postnatal short stature and congenital heart defects in 3/3 published, unrelated individuals.

PMID 33369061 Gileta et al 2021 - report x1 patient. Female proband was compound heterozygote for a nonsense variant and a multiexonic deletion of SEMA3A. Presents with postnatal short stature, congenital cardiac anomalies, dysmorphic features, hypogonadotrophic hypogonadism and anosmia.

PMID 28075028 Baumann et al 2017 - report x1 patient. Homozygous LoF variants identified in a proband from a consanguineous Turkish family. Noted at birth to have a high-positioned scapulae, deformed ribs and a lateral clavicular hook. The patient also had upper/lower limb contractures and aberrant right subclavian artery. Mild facial dysmorphism, micropenis and hypogonadotrophic hypogonadism also noted in the first week of life. Postnatal short stature (length 50cm at term birth)

PMID 24124006 Hofmann et al 2013 - first reported biallelic variants in a proband with postnatal short stature, skeletal anomalies of the thorax, congenital heart
defect and camptodactyly
Sources: Literature
Congenital Heart Defect v0.189 SPRED2 Zornitza Stark Phenotypes for gene: SPRED2 were changed from Rasopathy; developmental delay; intellectual disability; cardiac defects; short stature; skeletal anomalies; a typical facial gestalt to Noonan syndrome 14, MIM# 619745
Congenital Heart Defect v0.188 SPRED2 Zornitza Stark reviewed gene: SPRED2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Noonan syndrome 14, MIM# 619745; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.188 HYAL2 Zornitza Stark Marked gene: HYAL2 as ready
Congenital Heart Defect v0.188 HYAL2 Zornitza Stark Gene: hyal2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.188 HYAL2 Zornitza Stark Classified gene: HYAL2 as Green List (high evidence)
Congenital Heart Defect v0.188 HYAL2 Zornitza Stark Gene: hyal2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.187 HYAL2 Krithika Murali gene: HYAL2 was added
gene: HYAL2 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: HYAL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HYAL2 were set to 34906488; 28081210; 23172227; 26515055
Phenotypes for gene: HYAL2 were set to Cleft lip and palate; cor triatriatum; congenital cardiac malformations
Review for gene: HYAL2 was set to GREEN
Added comment: Combined reported phenotypic features of 17 individuals from both studies
• Hyperterlorism 13/16
• External ear anomalies – 11/14
• Cleft lip/palate – 10/17
• Micrognathia – 9/14
• Cardiac anomalies 12/17
• Frontal bossing 5/14
• Ptosis 5/13
• Pectus excavatum 7/16
• Myopia 11/11
• Cataract 2/8
• Hearing loss 7/16
Sources: Literature
Congenital Heart Defect v0.187 HAND2 Zornitza Stark Marked gene: HAND2 as ready
Congenital Heart Defect v0.187 HAND2 Zornitza Stark Gene: hand2 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.187 HAND2 Zornitza Stark Phenotypes for gene: HAND2 were changed from to Congenital heart disease
Congenital Heart Defect v0.186 HAND2 Zornitza Stark Publications for gene: HAND2 were set to
Congenital Heart Defect v0.185 HAND2 Zornitza Stark Mode of inheritance for gene: HAND2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.184 HAND2 Zornitza Stark Classified gene: HAND2 as Amber List (moderate evidence)
Congenital Heart Defect v0.184 HAND2 Zornitza Stark Gene: hand2 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.183 HAND1 Zornitza Stark Phenotypes for gene: HAND1 were changed from Congenital heart disease to Congenital heart disease, MONDO:0005453
Congenital Heart Defect v0.182 HAND1 Zornitza Stark Marked gene: HAND1 as ready
Congenital Heart Defect v0.182 HAND1 Zornitza Stark Gene: hand1 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.182 HAND1 Zornitza Stark Phenotypes for gene: HAND1 were changed from to Congenital heart disease
Congenital Heart Defect v0.181 HAND1 Zornitza Stark Publications for gene: HAND1 were set to
Congenital Heart Defect v0.180 HAND1 Zornitza Stark Mode of inheritance for gene: HAND1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.179 HAND1 Zornitza Stark Classified gene: HAND1 as Amber List (moderate evidence)
Congenital Heart Defect v0.179 HAND1 Zornitza Stark Gene: hand1 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.178 GATA5 Zornitza Stark Marked gene: GATA5 as ready
Congenital Heart Defect v0.178 GATA5 Zornitza Stark Gene: gata5 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.178 GATA5 Zornitza Stark Phenotypes for gene: GATA5 were changed from to Congenital heart defects, multiple types, 5 - #617912
Congenital Heart Defect v0.177 GATA5 Zornitza Stark Publications for gene: GATA5 were set to
Congenital Heart Defect v0.176 GATA5 Zornitza Stark Mode of inheritance for gene: GATA5 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital Heart Defect v0.175 GATA5 Zornitza Stark Classified gene: GATA5 as Amber List (moderate evidence)
Congenital Heart Defect v0.175 GATA5 Zornitza Stark Gene: gata5 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.174 FOXH1 Zornitza Stark Marked gene: FOXH1 as ready
Congenital Heart Defect v0.174 FOXH1 Zornitza Stark Gene: foxh1 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.174 FOXH1 Zornitza Stark Phenotypes for gene: FOXH1 were changed from to Congenital heart disease
Congenital Heart Defect v0.173 FOXH1 Zornitza Stark Publications for gene: FOXH1 were set to
Congenital Heart Defect v0.172 FOXH1 Zornitza Stark Mode of inheritance for gene: FOXH1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.171 FOXH1 Zornitza Stark Classified gene: FOXH1 as Amber List (moderate evidence)
Congenital Heart Defect v0.171 FOXH1 Zornitza Stark Gene: foxh1 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.170 HAND2 Krithika Murali reviewed gene: HAND2: Rating: AMBER; Mode of pathogenicity: None; Publications: 26865696, 32134193, 26676105, 30217752, 20819618; Phenotypes: Congenital heart disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.170 TKT Zornitza Stark Marked gene: TKT as ready
Congenital Heart Defect v0.170 TKT Zornitza Stark Gene: tkt has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.170 TKT Zornitza Stark Classified gene: TKT as Amber List (moderate evidence)
Congenital Heart Defect v0.170 TKT Zornitza Stark Gene: tkt has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.169 TKT Zornitza Stark gene: TKT was added
gene: TKT was added to Congenital Heart Defect. Sources: Expert Review
Mode of inheritance for gene: TKT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TKT were set to 27259054
Phenotypes for gene: TKT were set to Short stature, developmental delay, and congenital heart defects; OMIM #617044
Review for gene: TKT was set to AMBER
Added comment: Boyle et al. (2016) reported 3 families with 5 affected individuals with proportionate short stature, developmental delay, and congenital heart defects. Enzymatic testing confirmed significantly reduced transketolase activity. Elevated urinary excretion of erythritol, arabitol, ribitol, and pent(ul)ose-5-phosphates was detected, as well as elevated amounts of erythritol, arabitol, and ribitol in the plasma of affected individuals. Transketolase deficiency reduces NADPH synthesis and nucleic acid synthesis and cell division.

Two of the families had the same variant ?founder.
Sources: Expert Review
Congenital Heart Defect v0.168 HAND1 Krithika Murali reviewed gene: HAND1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31286141, 29016838, 29317578, 29179274, 28112363, 27942761, 26581070; Phenotypes: Congenital heart disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.168 GATA5 Krithika Murali reviewed gene: GATA5: Rating: AMBER; Mode of pathogenicity: None; Publications: 28180938, 27066509, 34461831, 30229885, 28285006, 25543888, 25515806, 24796370, 23295592, 23289003, 22961344; Phenotypes: Congenital heart defects, multiple types, 5 - #617912; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital Heart Defect v0.168 FOXH1 Krithika Murali reviewed gene: FOXH1: Rating: AMBER; Mode of pathogenicity: None; Publications: 18538293, 19933292, 32003456, 12094232, 16304598; Phenotypes: Congenital heart disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.168 NKX2-6 Zornitza Stark Marked gene: NKX2-6 as ready
Congenital Heart Defect v0.168 NKX2-6 Zornitza Stark Gene: nkx2-6 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.168 NKX2-6 Zornitza Stark Phenotypes for gene: NKX2-6 were changed from to Conotruncal heart malformations - MIM#217095; Persistent truncus arteriosus - MIM#217095
Congenital Heart Defect v0.167 NKX2-6 Zornitza Stark Publications for gene: NKX2-6 were set to
Congenital Heart Defect v0.166 NKX2-6 Zornitza Stark Mode of inheritance for gene: NKX2-6 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.165 NKX2-6 Krithika Murali reviewed gene: NKX2-6: Rating: GREEN; Mode of pathogenicity: None; Publications: 24421281, 15649947, 32198970, 25380965, 25319568; Phenotypes: Conotruncal heart malformations - MIM#217095, Persistent truncus arteriosus - MIM#217095; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.165 TLL1 Zornitza Stark Phenotypes for gene: TLL1 were changed from to Atrial septal defect 6 MIM#613087
Congenital Heart Defect v0.164 MIB1 Zornitza Stark Classified gene: MIB1 as Amber List (moderate evidence)
Congenital Heart Defect v0.164 MIB1 Zornitza Stark Gene: mib1 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.163 MIB1 Zornitza Stark changed review comment from: Established congenital cardiac disease gene. PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 11 de novo variants (1 frameshift, 2 missense, 2 splice acceptor, 1 splice donor, 5 stopgain) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Expert Review; to: Li 2018 (PMID: 30322850):
- in 4 CHD patients: p.Q237H (gv2v3 absent), p.W271G (gv2v3 absent), p.S520R (v2 5 hets) and p.T312Kfs*55 (NMD-pred, absent but many comparables in gnomAD).
- HEK293T cells transfection studies showed: T312Kfs*55 and W271G strongly impaired MIB1 function on substrate ubiquitination, while Q237H and S520R had slight or no obvious changes. Interaction between MIB1 and JAG1 is severely interrupted by p.T312Kfs*55 and p.W271G, but not really in the other 2 missense.
- Overexpression of wt or mutant in zebrafish all resulted in dysmorphic pheno, therefore not informative.

PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 11 de novo variants (1 frameshift, 2 missense, 2 splice acceptor, 1 splice donor, 5 stopgain) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Expert Review
Congenital Heart Defect v0.163 MIB1 Zornitza Stark edited their review of gene: MIB1: Changed rating: AMBER
Congenital Heart Defect v0.163 ACTC1 Zornitza Stark Tag founder tag was added to gene: ACTC1.
Congenital Heart Defect v0.163 ACTC1 Zornitza Stark Classified gene: ACTC1 as Amber List (moderate evidence)
Congenital Heart Defect v0.163 ACTC1 Zornitza Stark Gene: actc1 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.162 ACTC1 Zornitza Stark changed review comment from: Three families reported with congenital heart disease and variants in this gene. Note gene is also associated with cardiomyopathies.; to: Three families reported with congenital heart disease and variants in this gene. Note gene is also associated with cardiomyopathies.

Two of the families had the same founder variant.
Congenital Heart Defect v0.162 ACTC1 Zornitza Stark edited their review of gene: ACTC1: Changed rating: AMBER
Congenital Heart Defect v0.162 SMAD2 Zornitza Stark Phenotypes for gene: SMAD2 were changed from Aortic and arterial aneurysmal disease; connective tissue disease; congenital heart disease to Loeys-Dietz syndrome 6, MIM# 619656; Congenital heart defects, multiple types, 8, with or without heterotaxy, MIM# 619657
Congenital Heart Defect v0.161 SMAD2 Zornitza Stark edited their review of gene: SMAD2: Changed phenotypes: Loeys-Dietz syndrome 6, MIM# 619656, Congenital heart defects, multiple types, 8, with or without heterotaxy, MIM# 619657
Congenital Heart Defect v0.161 CCDC22 Zornitza Stark Marked gene: CCDC22 as ready
Congenital Heart Defect v0.161 CCDC22 Zornitza Stark Gene: ccdc22 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.161 CCDC22 Zornitza Stark Classified gene: CCDC22 as Green List (high evidence)
Congenital Heart Defect v0.161 CCDC22 Zornitza Stark Gene: ccdc22 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.160 CCDC22 Zornitza Stark gene: CCDC22 was added
gene: CCDC22 was added to Congenital Heart Defect. Sources: Expert Review
Mode of inheritance for gene: CCDC22 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: CCDC22 were set to 21826058; 24916641; 34020006; 33059814; 31971710
Phenotypes for gene: CCDC22 were set to Ritscher-Schinzel syndrome 2, MIM# 300963
Review for gene: CCDC22 was set to GREEN
Added comment: Ritscher-Schinzel syndrome-2 is an X-linked recessive syndromic form of intellectual disability associated with posterior fossa defects, cardiac malformations, and minor abnormalities of the face and distal extremities. At least 5 unrelated families reported.
Sources: Expert Review
Congenital Heart Defect v0.159 WLS Zornitza Stark Phenotypes for gene: WLS were changed from Syndromic structural birth defects to Zaki syndrome, MIM#619648
Congenital Heart Defect v0.158 WLS Zornitza Stark reviewed gene: WLS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Zaki syndrome, MIM#619648; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.158 TMEM260 Zornitza Stark changed review comment from: Seven unrelated families with complex severe congenital heart disease.
Sources: Expert list; to: Seven unrelated families with complex severe congenital heart disease. Clinical features: ventricular septal defects (12/12), mostly secondary to truncus arteriosus (10/12), elevated creatinine levels (6/12), horse-shoe kidneys (1/12) and renal cysts (1/12) in patients.
Sources: Expert list
Congenital Heart Defect v0.158 TMEM260 Zornitza Stark Classified gene: TMEM260 as Green List (high evidence)
Congenital Heart Defect v0.158 TMEM260 Zornitza Stark Gene: tmem260 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.157 TMEM260 Zornitza Stark changed review comment from: Two unrelated families with complex severe congenital heart disease.
Sources: Expert list; to: Seven unrelated families with complex severe congenital heart disease.
Sources: Expert list
Congenital Heart Defect v0.157 TMEM260 Zornitza Stark edited their review of gene: TMEM260: Changed rating: GREEN; Changed publications: 28318500, 34612517
Congenital Heart Defect v0.157 MMP15 Zornitza Stark Marked gene: MMP15 as ready
Congenital Heart Defect v0.157 MMP15 Zornitza Stark Gene: mmp15 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.157 MMP15 Zornitza Stark Classified gene: MMP15 as Amber List (moderate evidence)
Congenital Heart Defect v0.157 MMP15 Zornitza Stark Gene: mmp15 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.156 MMP15 Zornitza Stark gene: MMP15 was added
gene: MMP15 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: MMP15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MMP15 were set to 33875846
Phenotypes for gene: MMP15 were set to Cholestasis; Congenital heart disease
Review for gene: MMP15 was set to AMBER
Added comment: Three individuals from two families with bi-allelic variants and very similar phenotype including rare combination of symtoms (Alagille-like) cholestasis with hepatomegaly and congenital heart disease.
Sources: Literature
Congenital Heart Defect v0.155 TAB2 Zornitza Stark Marked gene: TAB2 as ready
Congenital Heart Defect v0.155 TAB2 Zornitza Stark Gene: tab2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.155 TAB2 Zornitza Stark Phenotypes for gene: TAB2 were changed from to Mitral valve disease, cardiomyopathy, short stature and hypermobility, Noonan syndrome-like; Congenital heart defects, nonsyndromic, 2 (MIM#614980)
Congenital Heart Defect v0.154 TAB2 Zornitza Stark Publications for gene: TAB2 were set to
Congenital Heart Defect v0.153 TAB2 Zornitza Stark Mode of inheritance for gene: TAB2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.152 TAB2 Zornitza Stark reviewed gene: TAB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34456334; Phenotypes: Mitral valve disease, cardiomyopathy, short stature and hypermobility, Noonan syndrome-like, Congenital heart defects, nonsyndromic, 2 (MIM#614980); Mode of inheritance: None
Congenital Heart Defect v0.152 TAB2 Chern Lim edited their review of gene: TAB2: Changed phenotypes: Mitral valve disease, cardiomyopathy, short stature and hypermobility, Noonan syndrome-like, Congenital heart defects, nonsyndromic, 2 (MIM#614980)
Congenital Heart Defect v0.152 TAB2 Chern Lim reviewed gene: TAB2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital heart defects, nonsyndromic, 2 (MIM#614980); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Congenital Heart Defect v0.152 SMAD2 Zornitza Stark Marked gene: SMAD2 as ready
Congenital Heart Defect v0.152 SMAD2 Zornitza Stark Gene: smad2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.152 SMAD2 Zornitza Stark Classified gene: SMAD2 as Green List (high evidence)
Congenital Heart Defect v0.152 SMAD2 Zornitza Stark Gene: smad2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.151 SMAD2 Zornitza Stark gene: SMAD2 was added
gene: SMAD2 was added to Congenital Heart Defect. Sources: Expert Review
Mode of inheritance for gene: SMAD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMAD2 were set to 29967133; 30157302; 23665959
Phenotypes for gene: SMAD2 were set to Aortic and arterial aneurysmal disease; connective tissue disease; congenital heart disease
Review for gene: SMAD2 was set to GREEN
Added comment: PMID: 30157302 - Two distinct phenotypes associated with pathogenic variants in SMAD2: complex congenital heart disease with or without laterality defects and other congenital anomalies, and a late-onset vascular phenotype characterized by arterial aneurysms with connective tissue abnormalities. No genotype/phenotype correlation has been established so far.

PMID: 30157302, PMID: 23665959 - 5 individuals reported with the CHD phenotype
Sources: Expert Review
Congenital Heart Defect v0.150 MAPKAPK5 Zornitza Stark Marked gene: MAPKAPK5 as ready
Congenital Heart Defect v0.150 MAPKAPK5 Zornitza Stark Gene: mapkapk5 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.150 MAPKAPK5 Zornitza Stark Classified gene: MAPKAPK5 as Green List (high evidence)
Congenital Heart Defect v0.150 MAPKAPK5 Zornitza Stark Gene: mapkapk5 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.149 MAPKAPK5 Zornitza Stark gene: MAPKAPK5 was added
gene: MAPKAPK5 was added to Congenital Heart Defect. Sources: Expert Review
Mode of inheritance for gene: MAPKAPK5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAPKAPK5 were set to 33442026
Phenotypes for gene: MAPKAPK5 were set to Developmental delay, variable brain anomalies, congenital heart defects, dysmorphic
Review for gene: MAPKAPK5 was set to GREEN
Added comment: 3 individuals from 2 families with severe developmental delay, variable brain anomalies, congenital heart defects, dysmorphic facial features, and a distinctive type of synpolydactyly with an additional hypoplastic digit between the fourth and fifth digits of hands and/or feet. Exome sequencing identified different homozygous truncating variants in MAPKAPK5 in both families, segregating with disease and unaffected parents as carriers.

Patient-derived cells showed no expression of MAPKAPK5 protein isoforms and reduced levels of the MAPKAPK5-interacting protein ERK3. F-actin recovery after latrunculin B treatment was found to be less efficient in patient-derived fibroblasts than in control cells, supporting a role of MAPKAPK5 in F-actin polymerization.
Sources: Expert Review
Congenital Heart Defect v0.148 NADSYN1 Zornitza Stark Phenotypes for gene: NADSYN1 were changed from Multiple congenital abnormalities; absent kidneys; cardiac; limb; vertebral to Vertebral, cardiac, renal, and limb defects syndrome 3, MONDO:0030077; Vertebral, cardiac, renal, and limb defects syndrome 3, OMIM:618845
Congenital Heart Defect v0.147 NADSYN1 Zornitza Stark Marked gene: NADSYN1 as ready
Congenital Heart Defect v0.147 NADSYN1 Zornitza Stark Gene: nadsyn1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.147 NADSYN1 Zornitza Stark Classified gene: NADSYN1 as Green List (high evidence)
Congenital Heart Defect v0.147 NADSYN1 Zornitza Stark Gene: nadsyn1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.146 NADSYN1 Zornitza Stark gene: NADSYN1 was added
gene: NADSYN1 was added to Congenital Heart Defect. Sources: Expert Review
Mode of inheritance for gene: NADSYN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NADSYN1 were set to 31883644
Phenotypes for gene: NADSYN1 were set to Multiple congenital abnormalities; absent kidneys; cardiac; limb; vertebral
Review for gene: NADSYN1 was set to GREEN
Added comment: Five individuals from four unrelated families.
Sources: Expert Review
Congenital Heart Defect v0.145 MEIS2 Zornitza Stark Marked gene: MEIS2 as ready
Congenital Heart Defect v0.145 MEIS2 Zornitza Stark Gene: meis2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.145 MEIS2 Zornitza Stark Phenotypes for gene: MEIS2 were changed from to Cleft palate, cardiac defects, and mental retardation (MIM#600987)
Congenital Heart Defect v0.144 MEIS2 Zornitza Stark Publications for gene: MEIS2 were set to
Congenital Heart Defect v0.143 MEIS2 Zornitza Stark Mode of inheritance for gene: MEIS2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.142 MEIS2 Zornitza Stark reviewed gene: MEIS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33427397, 25712757; Phenotypes: Cleft palate, cardiac defects, and mental retardation (MIM#600987); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.142 DLL4 Zornitza Stark Marked gene: DLL4 as ready
Congenital Heart Defect v0.142 DLL4 Zornitza Stark Gene: dll4 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.142 DLL4 Zornitza Stark Phenotypes for gene: DLL4 were changed from to Adams-Oliver syndrome 6 MIM#616589
Congenital Heart Defect v0.141 DLL4 Zornitza Stark Publications for gene: DLL4 were set to
Congenital Heart Defect v0.140 DLL4 Zornitza Stark Mode of inheritance for gene: DLL4 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.139 DLL4 Zornitza Stark reviewed gene: DLL4: Rating: GREEN; Mode of pathogenicity: None; Publications: 26299364, 33899511, 31261205, 29924900; Phenotypes: Adams-Oliver syndrome 6 MIM#616589; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.139 HNRNPK Zornitza Stark Marked gene: HNRNPK as ready
Congenital Heart Defect v0.139 HNRNPK Zornitza Stark Gene: hnrnpk has been classified as Green List (High Evidence).
Congenital Heart Defect v0.139 HNRNPK Zornitza Stark Classified gene: HNRNPK as Green List (high evidence)
Congenital Heart Defect v0.139 HNRNPK Zornitza Stark Gene: hnrnpk has been classified as Green List (High Evidence).
Congenital Heart Defect v0.138 HNRNPK Ain Roesley gene: HNRNPK was added
gene: HNRNPK was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: HNRNPK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: HNRNPK were set to Au-Kline syndrome MIM#616580
Penetrance for gene: HNRNPK were set to Complete
Review for gene: HNRNPK was set to GREEN
gene: HNRNPK was marked as current diagnostic
Added comment: Caused by de novo variants.

Review of >20 individuals in GeneReviews:
- Brain anomalies have been identified in several individuals. The most common abnormalities were heterotopia and thinning of the corpus callosum.
- Congenital heart disease is present in approximately 75% of individuals with AKS
- Hydronephrosis is present in up to 75% of individuals
- Craniosynostosis is present in approximately 1/3 of individuals with AKS.
- More than half of individuals with AKS have scoliosis and congenital hip dysplasia
- Palate abnormalities, which include cleft palate, high-arched or narrow palate, and bifid uvula, are common.
Sources: Literature
Congenital Heart Defect v0.138 DNAH11 Zornitza Stark Marked gene: DNAH11 as ready
Congenital Heart Defect v0.138 DNAH11 Zornitza Stark Gene: dnah11 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.138 DNAH11 Zornitza Stark Phenotypes for gene: DNAH11 were changed from Congenital heart diseases; heterotaxy to Congenital heart diseases; Ciliary dyskinesia, primary, 7, with or without situs inversus, MIM# 611884
Congenital Heart Defect v0.137 DNAH11 Zornitza Stark Publications for gene: DNAH11 were set to PMID: 31040315; 32633470
Congenital Heart Defect v0.136 DNAH11 Zornitza Stark Classified gene: DNAH11 as Green List (high evidence)
Congenital Heart Defect v0.136 DNAH11 Zornitza Stark Gene: dnah11 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.135 DNAH11 Zornitza Stark reviewed gene: DNAH11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ciliary dyskinesia, primary, 7, with or without situs inversus, MIM# 611884; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.135 DNAH11 Daniel Flanagan gene: DNAH11 was added
gene: DNAH11 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: DNAH11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH11 were set to PMID: 31040315; 32633470
Phenotypes for gene: DNAH11 were set to Congenital heart diseases; heterotaxy
Review for gene: DNAH11 was set to GREEN
Added comment: Compound het DNAH11 variants reported in 7 families with congenital heart diseases and heterotaxy.

Biallelic DNAH11 variants commonly reported in patients with primary ciliary dyskinesia.
Sources: Literature
Congenital Heart Defect v0.135 SPRED2 Zornitza Stark Marked gene: SPRED2 as ready
Congenital Heart Defect v0.135 SPRED2 Zornitza Stark Gene: spred2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.135 SPRED2 Zornitza Stark Phenotypes for gene: SPRED2 were changed from developmental delay; intellectual disability; cardiac defects; short stature; skeletal anomalies; a typical facial gestalt to Rasopathy; developmental delay; intellectual disability; cardiac defects; short stature; skeletal anomalies; a typical facial gestalt
Congenital Heart Defect v0.134 SPRED2 Zornitza Stark Classified gene: SPRED2 as Green List (high evidence)
Congenital Heart Defect v0.134 SPRED2 Zornitza Stark Gene: spred2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.133 SPRED2 Dean Phelan gene: SPRED2 was added
gene: SPRED2 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: SPRED2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPRED2 were set to PMID: 34626534
Phenotypes for gene: SPRED2 were set to developmental delay; intellectual disability; cardiac defects; short stature; skeletal anomalies; a typical facial gestalt
Review for gene: SPRED2 was set to GREEN
Added comment: PMID: 34626534
Homozygosity for three different variants c.187C>T (p.Arg63∗), c.299T>C (p.Leu100Pro), and c.1142_1143delTT (p.Leu381Hisfs∗95) were identified in four subjects from three families. All variants severely affected protein stability, causing accelerated degradation, and variably perturbed SPRED2 functional behaviour. The clinical phenotype of the four affected individuals included developmental delay, intellectual disability, cardiac defects, short stature, skeletal anomalies, and a typical facial gestalt as major features, without the occurrence of the distinctive skin signs characterizing Legius syndrome.
Sources: Literature
Congenital Heart Defect v0.133 BCL9L Zornitza Stark Marked gene: BCL9L as ready
Congenital Heart Defect v0.133 BCL9L Zornitza Stark Gene: bcl9l has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.133 BCL9L Zornitza Stark Publications for gene: BCL9L were set to 23035047; 8757136
Congenital Heart Defect v0.132 BCL9L Zornitza Stark Classified gene: BCL9L as Amber List (moderate evidence)
Congenital Heart Defect v0.132 BCL9L Zornitza Stark Gene: bcl9l has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.131 BCL9L Zornitza Stark reviewed gene: BCL9L: Rating: AMBER; Mode of pathogenicity: None; Publications: 30366904; Phenotypes: Congenital heart defects; Mode of inheritance: None
Congenital Heart Defect v0.131 BCL9L Krithika Murali gene: BCL9L was added
gene: BCL9L was added to Congenital Heart Defect. Sources: Expert list,Literature,Other
Mode of inheritance for gene: BCL9L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BCL9L were set to 23035047; 8757136
Phenotypes for gene: BCL9L were set to Congenital Heart Disease; Heterotaxy
Review for gene: BCL9L was set to AMBER
Added comment: Novel gene disease association. Saunders et al. 2012 (PMID: 23035047) report biallelic BCL9L variants in 2 affected brothers with heterotaxy and congenital heart disease, heterozygous in unaffected parents. Functional evidence in zebrafish (PMID 8757136)
Sources: Expert list, Literature, Other
Congenital Heart Defect v0.131 WLS Zornitza Stark Marked gene: WLS as ready
Congenital Heart Defect v0.131 WLS Zornitza Stark Gene: wls has been classified as Green List (High Evidence).
Congenital Heart Defect v0.131 WLS Zornitza Stark Classified gene: WLS as Green List (high evidence)
Congenital Heart Defect v0.131 WLS Zornitza Stark Gene: wls has been classified as Green List (High Evidence).
Congenital Heart Defect v0.130 WLS Teresa Zhao gene: WLS was added
gene: WLS was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: WLS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WLS were set to PMID: 34587386
Phenotypes for gene: WLS were set to Syndromic structural birth defects
Review for gene: WLS was set to GREEN
Added comment: - Homozygous mutations in 10 affected persons from 5 unrelated families.
- Patients had multiorgan defects, including microcephal, facial dysmorphism, foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects.
- The mutations affected WLS protein stability and Wnt signaling. Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis.
Sources: Literature
Congenital Heart Defect v0.130 SPEN Zornitza Stark Marked gene: SPEN as ready
Congenital Heart Defect v0.130 SPEN Zornitza Stark Gene: spen has been classified as Green List (High Evidence).
Congenital Heart Defect v0.130 SPEN Zornitza Stark Classified gene: SPEN as Green List (high evidence)
Congenital Heart Defect v0.130 SPEN Zornitza Stark Gene: spen has been classified as Green List (High Evidence).
Congenital Heart Defect v0.129 SPEN Elena Savva gene: SPEN was added
gene: SPEN was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: SPEN was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPEN were set to PMID: 33596411
Phenotypes for gene: SPEN were set to Radio-Tartaglia syndrome MIM#619312
Review for gene: SPEN was set to GREEN
gene: SPEN was marked as current diagnostic
Added comment: PMID: 33596411
- 34 individuals with truncating variants in SPEN reported, most are de novo variants.
- Clinical profile includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females.
- Authors showed haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females.
Sources: Literature
Congenital Heart Defect v0.129 ZMYM2 Zornitza Stark Marked gene: ZMYM2 as ready
Congenital Heart Defect v0.129 ZMYM2 Zornitza Stark Gene: zmym2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.129 ZMYM2 Zornitza Stark Classified gene: ZMYM2 as Green List (high evidence)
Congenital Heart Defect v0.129 ZMYM2 Zornitza Stark Gene: zmym2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.128 ZMYM2 Zornitza Stark gene: ZMYM2 was added
gene: ZMYM2 was added to Congenital Heart Defect. Sources: Expert Review
Mode of inheritance for gene: ZMYM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZMYM2 were set to 32891193
Phenotypes for gene: ZMYM2 were set to Neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities, MIM# 619522
Review for gene: ZMYM2 was set to GREEN
Added comment: Connaughton et al (2020 - PMID: 32891193) report on 19 individuals (from 15 unrelated families) with heterozygous pathogenic ZMYM2 variants.

Affected individuals from 7 families presented with CAKUT while all of them displayed extra-renal features. Neurological manifestations were reported in 16 individuals from 14 families (data not available for 1 fam), among others hypotonia (3/14 fam), speech delay (4/14 fam), global DD (9/14 fam), ID (4/14 fam), microcephaly (4/14 fam). ASD was reported in 4 fam (4 indiv). Seizures were reported in 2 fam (2 indiv). Variable other features included cardiac defects, facial dysmorphisms, small hands and feet with dys-/hypo-plastic nails and clinodactyly.

14 pLoF variants were identified, in most cases as de novo events (8 fam). In 2 families the variant was inherited from an affected parent. Germline mosaicism occurred in 1 family.

The human disease features were recapitulated in a X. tropicalis morpholino knockdown, with expression of truncating variants failing to rescue renal and craniofacial defects. Heterozygous Zmym2-deficient mice also recapitulated the features of CAKUT.

ZMYM2 (previously ZNF198) encodes a nuclear zinc finger protein localizing to the nucleus (and PML nuclear body).

It has previously been identified as transcriptional corepressor interacting with nuclear receptors and the LSD1-CoREST-HDAC1 complex. It has also been shown to interact with FOXP transcription factors.

The authors provide evidence for loss of interaction of the truncated ZMYM2 with FOXP1 (mutations in the latter having recently been reported in syndromic CAKUT).
Sources: Expert Review
Congenital Heart Defect v0.127 ZNF699 Zornitza Stark Marked gene: ZNF699 as ready
Congenital Heart Defect v0.127 ZNF699 Zornitza Stark Gene: znf699 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.127 ZNF699 Zornitza Stark Classified gene: ZNF699 as Green List (high evidence)
Congenital Heart Defect v0.127 ZNF699 Zornitza Stark Gene: znf699 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.126 ZNF699 Zornitza Stark gene: ZNF699 was added
gene: ZNF699 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: ZNF699 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF699 were set to 33875846
Phenotypes for gene: ZNF699 were set to DEGCAGS syndrome, MIM# 619488
Review for gene: ZNF699 was set to GREEN
Added comment: DEGCAGS syndrome is a neurodevelopmental disorder characterized by global developmental delay, coarse and dysmorphic facial features, and poor growth and feeding apparent from infancy. Affected individuals have variable systemic manifestations often with significant structural defects of the cardiovascular, genitourinary, gastrointestinal, and/or skeletal systems. Additional features may include sensorineural hearing loss, hypotonia, anaemia or pancytopaenia, and immunodeficiency with recurrent infections.

12 unrelated families reported, 5 different homozygous frameshift variants.
Sources: Literature
Congenital Heart Defect v0.125 STK4 Zornitza Stark Marked gene: STK4 as ready
Congenital Heart Defect v0.125 STK4 Zornitza Stark Gene: stk4 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.125 STK4 Zornitza Stark Classified gene: STK4 as Green List (high evidence)
Congenital Heart Defect v0.125 STK4 Zornitza Stark Gene: stk4 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.124 STK4 Danielle Ariti gene: STK4 was added
gene: STK4 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: STK4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STK4 were set to 22294732; 26117625; 22174160; 22952854
Phenotypes for gene: STK4 were set to T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations MIM# 614868; CD4/CD8 lymphopaenia; cardiac malformations; reduced naïve T cells; increased TEM and TEMRA cells; poor T cell Proliferation; Reduced memory B cells; Reduced IgM, increased IgG, IgA, IgE; impaired antibody responses; intermittent neutropaenia; bacterial/ viral/ fungal infections; autoimmune cytopaenias; mucocutaneous candidiasis; cutaneous warts
Review for gene: STK4 was set to GREEN
Added comment: 12 individuals from 5 unrelated families have been reported with STK4 deficiency; two mouse model.

Homozygous and compound heterozygous (deletion, missense and nonsense) variants have been identified, resulting in premature stop codons and reduced protein.

All individuals displayed a similar immunological phenotype, characterised by naive CD4+ and CD8+ T-cell lymphopaenia in particular. Other typical features included cardiac malformations, recurrent bacterial/viral infections, mucocutaneous candidiasis and cutaneous warts.
Sources: Literature
Congenital Heart Defect v0.124 MYH7 Zornitza Stark Marked gene: MYH7 as ready
Congenital Heart Defect v0.124 MYH7 Zornitza Stark Gene: myh7 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.124 MYH7 Zornitza Stark Phenotypes for gene: MYH7 were changed from to Ebstein anomaly
Congenital Heart Defect v0.123 MYH7 Zornitza Stark Publications for gene: MYH7 were set to
Congenital Heart Defect v0.122 MYH7 Zornitza Stark Mode of pathogenicity for gene: MYH7 was changed from to Other
Congenital Heart Defect v0.121 MYH7 Zornitza Stark Mode of inheritance for gene: MYH7 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.120 MYH7 Teresa Zhao reviewed gene: MYH7: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 21127202; Phenotypes: Ebstein anomaly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital Heart Defect v0.120 UBR1 Zornitza Stark Marked gene: UBR1 as ready
Congenital Heart Defect v0.120 UBR1 Zornitza Stark Gene: ubr1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.120 UBR1 Zornitza Stark Phenotypes for gene: UBR1 were changed from to Johanson-Blizzard syndrome (MIM#243800)
Congenital Heart Defect v0.119 UBR1 Zornitza Stark Publications for gene: UBR1 were set to
Congenital Heart Defect v0.118 UBR1 Zornitza Stark Mode of inheritance for gene: UBR1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.117 UBR1 Zornitza Stark reviewed gene: UBR1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Johanson-Blizzard syndrome (MIM#243800); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.117 UBR1 Teresa Zhao reviewed gene: UBR1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 24599544; Phenotypes: Johanson-Blizzard syndrome (MIM#243800); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.117 IGF2 Zornitza Stark Marked gene: IGF2 as ready
Congenital Heart Defect v0.117 IGF2 Zornitza Stark Gene: igf2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.117 IGF2 Zornitza Stark Classified gene: IGF2 as Green List (high evidence)
Congenital Heart Defect v0.117 IGF2 Zornitza Stark Gene: igf2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.116 IGF2 Elena Savva gene: IGF2 was added
gene: IGF2 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: IGF2 was set to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Publications for gene: IGF2 were set to PMID: 31544945
Phenotypes for gene: IGF2 were set to Silver-Russell syndrome 3 MIM#616489
Review for gene: IGF2 was set to GREEN
Added comment: PMID: 31544945 - cardiovascular anomalies reported in 50% of patients
Sources: Literature
Congenital Heart Defect v0.116 PRKD1 Zornitza Stark Phenotypes for gene: PRKD1 were changed from Congenital heart defects and ectodermal dysplasia, 617364 to Congenital heart defects and ectodermal dysplasia, 617364; Autosomal Recessive Congenital Heart Disease
Congenital Heart Defect v0.115 PRKD1 Zornitza Stark Publications for gene: PRKD1 were set to 27479907; 32817298
Congenital Heart Defect v0.114 PRKD1 Zornitza Stark Mode of inheritance for gene: PRKD1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital Heart Defect v0.113 PRKD1 Kristin Rigbye reviewed gene: PRKD1: Rating: AMBER; Mode of pathogenicity: None; Publications: 25713110, 33919081; Phenotypes: Autosomal Recessive Congenital Heart Disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.113 SLC37A4 Sue White Marked gene: SLC37A4 as ready
Congenital Heart Defect v0.113 SLC37A4 Sue White Gene: slc37a4 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.113 SLC37A4 Sue White Classified gene: SLC37A4 as Green List (high evidence)
Congenital Heart Defect v0.113 SLC37A4 Sue White Gene: slc37a4 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.112 SLC37A4 Paul De Fazio gene: SLC37A4 was added
gene: SLC37A4 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: SLC37A4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SLC37A4 were set to 33964207
Phenotypes for gene: SLC37A4 were set to Congenital disorder of glycosylation; liver dysfunction; coagulation deficiency
Review for gene: SLC37A4 was set to GREEN
gene: SLC37A4 was marked as current diagnostic
Added comment: 7 patients from 4 families, additional to the two reported previously, described with the same recurrent c.1267C>T (p.R423*) variant with liver dysfunction multifactorial coagulation deficiency and cardiac issues. Serum samples from affected individuals showed profound accumulation of both high mannose and hybrid type N-glycans. Hepatoma cell-line studies support the pathogenicity of the variant.
Sources: Literature
Congenital Heart Defect v0.112 ZEB2 Zornitza Stark Tag SV/CNV tag was added to gene: ZEB2.
Congenital Heart Defect v0.112 ZEB2 Zornitza Stark Marked gene: ZEB2 as ready
Congenital Heart Defect v0.112 ZEB2 Zornitza Stark Gene: zeb2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.112 ZEB2 Zornitza Stark Phenotypes for gene: ZEB2 were changed from to Mowat-Wilson syndrome, MIM# 235730; MONDO:0009341
Congenital Heart Defect v0.111 ZEB2 Zornitza Stark Publications for gene: ZEB2 were set to
Congenital Heart Defect v0.110 ZEB2 Zornitza Stark Mode of inheritance for gene: ZEB2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.109 ZEB2 Zornitza Stark reviewed gene: ZEB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29300384, 27831545, 24715670, 19215041, 17958891; Phenotypes: Mowat-Wilson syndrome, MIM# 235730, MONDO:0009341; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.109 EHMT1 Zornitza Stark Tag SV/CNV tag was added to gene: EHMT1.
Congenital Heart Defect v0.109 EHMT1 Zornitza Stark Marked gene: EHMT1 as ready
Congenital Heart Defect v0.109 EHMT1 Zornitza Stark Gene: ehmt1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.109 EHMT1 Zornitza Stark Phenotypes for gene: EHMT1 were changed from to Kleefstra syndrome 1, MIM# 610253; MONDO:0027407
Congenital Heart Defect v0.108 EHMT1 Zornitza Stark Publications for gene: EHMT1 were set to
Congenital Heart Defect v0.107 EHMT1 Zornitza Stark Mode of inheritance for gene: EHMT1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.106 EHMT1 Zornitza Stark reviewed gene: EHMT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16826528, 19264732, 19293338, 22670143, 30448833; Phenotypes: Kleefstra syndrome 1, MIM# 610253, MONDO:0027407; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.106 TRAF7 Zornitza Stark Marked gene: TRAF7 as ready
Congenital Heart Defect v0.106 TRAF7 Zornitza Stark Gene: traf7 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.106 TRAF7 Zornitza Stark Classified gene: TRAF7 as Green List (high evidence)
Congenital Heart Defect v0.106 TRAF7 Zornitza Stark Gene: traf7 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.105 TRAF7 Zornitza Stark gene: TRAF7 was added
gene: TRAF7 was added to Congenital Heart Defect. Sources: Expert Review
Mode of inheritance for gene: TRAF7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRAF7 were set to 32376980
Phenotypes for gene: TRAF7 were set to Cardiac, facial, and digital anomalies with developmental delay, MIM# 618164
Review for gene: TRAF7 was set to GREEN
Added comment: More than 40 individuals reported with DD/ID and a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent.
Sources: Expert Review
Congenital Heart Defect v0.104 MESP1 Zornitza Stark Marked gene: MESP1 as ready
Congenital Heart Defect v0.104 MESP1 Zornitza Stark Gene: mesp1 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.104 MESP1 Zornitza Stark Phenotypes for gene: MESP1 were changed from to Congenital heart disease
Congenital Heart Defect v0.103 MESP1 Zornitza Stark Publications for gene: MESP1 were set to
Congenital Heart Defect v0.102 MESP1 Zornitza Stark Mode of inheritance for gene: MESP1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.101 MESP1 Zornitza Stark Classified gene: MESP1 as Amber List (moderate evidence)
Congenital Heart Defect v0.101 MESP1 Zornitza Stark Gene: mesp1 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.100 MESP1 Zornitza Stark reviewed gene: MESP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 28677747, 28050627, 27185833, 26694203; Phenotypes: Congenital heart disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.100 ALDH1A2 Bryony Thompson Marked gene: ALDH1A2 as ready
Congenital Heart Defect v0.100 ALDH1A2 Bryony Thompson Gene: aldh1a2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.100 ALDH1A2 Bryony Thompson Classified gene: ALDH1A2 as Green List (high evidence)
Congenital Heart Defect v0.100 ALDH1A2 Bryony Thompson Gene: aldh1a2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.99 ALDH1A2 Bryony Thompson gene: ALDH1A2 was added
gene: ALDH1A2 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: ALDH1A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALDH1A2 were set to 33565183; 10192400
Phenotypes for gene: ALDH1A2 were set to Congenital heart defects; diaphragmatic eventration; pulmonary hypoplasia; dysmorphic features
Review for gene: ALDH1A2 was set to GREEN
Added comment: Two families, an Australian family with segregation of biallelic variants and an unrelated Italian proband with biallelic variants with similar phenotypes. Functional assays suggest the variants in the 2 families are hypomorphic. Knockout mouse model is embryonic lethal due utero defects in early heart morphogenesis.
Sources: Literature
Congenital Heart Defect v0.98 MIB1 Zornitza Stark Marked gene: MIB1 as ready
Congenital Heart Defect v0.98 MIB1 Zornitza Stark Gene: mib1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.98 MIB1 Zornitza Stark Classified gene: MIB1 as Green List (high evidence)
Congenital Heart Defect v0.98 MIB1 Zornitza Stark Gene: mib1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.97 MIB1 Zornitza Stark gene: MIB1 was added
gene: MIB1 was added to Congenital Heart Defect. Sources: Expert Review
Mode of inheritance for gene: MIB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MIB1 were set to 33057194
Phenotypes for gene: MIB1 were set to Congenital heart disease
Review for gene: MIB1 was set to GREEN
Added comment: Established congenital cardiac disease gene. PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 11 de novo variants (1 frameshift, 2 missense, 2 splice acceptor, 1 splice donor, 5 stopgain) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Expert Review
Congenital Heart Defect v0.97 MIB1 Zornitza Stark gene: MIB1 was added
gene: MIB1 was added to Congenital Heart Defect. Sources: Expert Review
Mode of inheritance for gene: MIB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MIB1 were set to 33057194
Phenotypes for gene: MIB1 were set to Congenital heart disease
Review for gene: MIB1 was set to GREEN
Added comment: Established congenital cardiac disease gene. PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 11 de novo variants (1 frameshift, 2 missense, 2 splice acceptor, 1 splice donor, 5 stopgain) identified in ~10,000 cases with developmental disorders (no other phenotype info provided).
Sources: Expert Review
Congenital Heart Defect v0.96 INVS Zornitza Stark Marked gene: INVS as ready
Congenital Heart Defect v0.96 INVS Zornitza Stark Gene: invs has been classified as Green List (High Evidence).
Congenital Heart Defect v0.96 INVS Zornitza Stark Phenotypes for gene: INVS were changed from to Nephronophthisis 2, infantile, (MIM#602088)
Congenital Heart Defect v0.95 INVS Zornitza Stark Publications for gene: INVS were set to
Congenital Heart Defect v0.94 INVS Zornitza Stark Mode of inheritance for gene: INVS was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.94 INVS Zornitza Stark Mode of inheritance for gene: INVS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.93 INVS Paul De Fazio reviewed gene: INVS: Rating: GREEN; Mode of pathogenicity: None; Publications: 12872123, 19177160; Phenotypes: Nephronophthisis 2, infantile, (MIM#602088); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Congenital Heart Defect v0.93 WBP11 Zornitza Stark Marked gene: WBP11 as ready
Congenital Heart Defect v0.93 WBP11 Zornitza Stark Gene: wbp11 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.93 WBP11 Zornitza Stark Classified gene: WBP11 as Green List (high evidence)
Congenital Heart Defect v0.93 WBP11 Zornitza Stark Gene: wbp11 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.92 WBP11 Zornitza Stark gene: WBP11 was added
gene: WBP11 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: WBP11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WBP11 were set to 33276377
Phenotypes for gene: WBP11 were set to Vertebral, cardiac, tracheoesophageal, renal, and limb defects, MIM# 619227
Review for gene: WBP11 was set to GREEN
Added comment: PMID: 33276377 - Martin et al 2020 - report 13 affected individuals from 7 unrelated families identified through various different cohort analysis (vertebral malformation, renal hypodysplasia, syndromic esophageal atresia, multiple congenital anomalies) in whom a WBP11 heterozygous variant is considered the top causative candidate. 5 identified variants were predicted to be protein truncating whilst the 6th was a missense variant. All variants are absent from population databases. In family 1, the variant was inherited from the apparently unaffected mother, indicating reduced penetrance, and phenotypic variance within families was observed. Phenotypes covered cardiac, vertebral, renal, craniofacial and gastrointestinal systems. At least at least 5 of the patients affected had features in three component organs so can be considered a VACTERL association. Wbp11 heterozygous null mice had vertebral and renal anomalies.
Sources: Literature
Congenital Heart Defect v0.91 PLD1 Zornitza Stark Tag founder tag was added to gene: PLD1.
Congenital Heart Defect v0.91 PLD1 Zornitza Stark Phenotypes for gene: PLD1 were changed from Cardiac valvular defect, developmental, MIM# 212093 to Cardiac valvular defect, developmental, MIM# 212093; neonatal cardiomyopathy
Congenital Heart Defect v0.90 PLD1 Zornitza Stark Publications for gene: PLD1 were set to 27799408
Congenital Heart Defect v0.89 PLD1 Zornitza Stark Classified gene: PLD1 as Green List (high evidence)
Congenital Heart Defect v0.89 PLD1 Zornitza Stark Gene: pld1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.88 PLD1 Zornitza Stark edited their review of gene: PLD1: Added comment: PMID 33645542: 31 individuals from 20 families reported, presenting predominantly with congenital cardiac valve defects and some with neonatal cardiomyopathy. p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%).; Changed rating: GREEN; Changed publications: 27799408, 33645542; Changed phenotypes: Cardiac valvular defect, developmental, MIM# 212093
Congenital Heart Defect v0.88 UBR7 Zornitza Stark Phenotypes for gene: UBR7 were changed from Intellectual disability; epilepsy; hypothyroidism; congenital anomalies; dysmorphic features to Li-Campeau syndrome, MIM# 619189; Intellectual disability; epilepsy; hypothyroidism; congenital anomalies; dysmorphic features
Congenital Heart Defect v0.87 UBR7 Zornitza Stark edited their review of gene: UBR7: Changed phenotypes: Li-Campeau syndrome, MIM# 619189, Intellectual disability, epilepsy, hypothyroidism, congenital anomalies, dysmorphic features
Congenital Heart Defect v0.87 HEY2 Zornitza Stark Marked gene: HEY2 as ready
Congenital Heart Defect v0.87 HEY2 Zornitza Stark Gene: hey2 has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.87 HEY2 Chirag Patel gene: HEY2 was added
gene: HEY2 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: HEY2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: HEY2 were set to PMID: 32820247
Phenotypes for gene: HEY2 were set to congenital heart defects and thoracic aortic aneurysms
Review for gene: HEY2 was set to RED
Added comment: A very large family affected by CHD and familial thoracic aortic aneurysms. Trio genome sequencing was carried out in an index patient with critical CHD, and family members had either exome or Sanger sequencing. Identified homozygous loss-of-function variant (c.318_319delAG, p.G108*) in HEY2 in 3 individuals in family with critical CHD, whereas the 20 heterozygous carriers show a spectrum of CVDs (CHD and FTAA, but varying expressivity and incomplete penetrance).

Other studies show that knockout of HEY2 in mice results in cardiovascular defects (CVDs), including septal defects, cardiomyopathy, a thin-walled aorta, and valve anomalies.
Sources: Literature
Congenital Heart Defect v0.86 UBR7 Zornitza Stark Marked gene: UBR7 as ready
Congenital Heart Defect v0.86 UBR7 Zornitza Stark Gene: ubr7 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.86 UBR7 Zornitza Stark Classified gene: UBR7 as Green List (high evidence)
Congenital Heart Defect v0.86 UBR7 Zornitza Stark Gene: ubr7 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.85 UBR7 Zornitza Stark gene: UBR7 was added
gene: UBR7 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: UBR7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBR7 were set to 33340455
Phenotypes for gene: UBR7 were set to Intellectual disability; epilepsy; hypothyroidism; congenital anomalies; dysmorphic features
Review for gene: UBR7 was set to GREEN
Added comment: Seven individuals from 6 unrelated families. All had developmental delay, and all males had urogenital anomalies, namely cryptorchidism in 5/6 and small penis in 1/6. Six individuals had seizures and hypotonia. Hypothyroidism was present in 4/7 individuals, and ptosis was noted in 6/7 individuals. Five individuals exhibited cardiac abnormalities: two had ventricular septal defect, one had atrial septal defect, one had a patent ductus arteriosus requiring surgery, and the other had a patent ductus arteriosus and a patent foramen ovale that both closed spontaneously. Five individuals had short stature (height < 3rd percentile). Physical examination revealed various dysmorphic features, including prominent forehead (3/7), hypertelorism (4/7), telecanthus (1/7), epicanthus(1/7), downslanting palpebral fissures (3/7), thick eyebrow (1/7), low-set ears (3/7), long philtrum (2/7), unilateral single transverse palmar crease (1/7), and hypertrichosis (1/7).
Sources: Literature
Congenital Heart Defect v0.84 Zornitza Stark removed gene:RPL3L from the panel
Congenital Heart Defect v0.83 FBRSL1 Zornitza Stark Marked gene: FBRSL1 as ready
Congenital Heart Defect v0.83 FBRSL1 Zornitza Stark Gene: fbrsl1 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.83 RPL3L Elena Savva Deleted their review
Congenital Heart Defect v0.83 FBRSL1 Sue White Classified gene: FBRSL1 as Amber List (moderate evidence)
Congenital Heart Defect v0.83 FBRSL1 Sue White Gene: fbrsl1 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.82 RPL3L Elena Savva gene: RPL3L was added
gene: RPL3L was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: RPL3L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPL3L were set to PMID: 32514796; 32870709
Phenotypes for gene: RPL3L were set to Neonatal dilated cardiomyopathy
Review for gene: RPL3L was set to GREEN
Added comment: PMID: 32514796 - 5 hom/chet individuals from three independent families who presented with severe neonatal dilated cardiomyopathy. Unaffected sibs were either carriers of a single variant or homozygous wildtype.

PMID: 32870709 - 1 hom patient w/ neonatal DCM
Sources: Literature
Congenital Heart Defect v0.82 FBRSL1 Elena Savva gene: FBRSL1 was added
gene: FBRSL1 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: FBRSL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FBRSL1 were set to PMID: 32424618
Phenotypes for gene: FBRSL1 were set to Malformation and intellectual disability syndrome
Review for gene: FBRSL1 was set to AMBER
Added comment: Three children with de novo PTCs that escape NMD, and an overlapping syndromic phenotype.
2/3 had heart defects, cleft palate and hearing impairment.
Variant pathogenicity supported by Xenopus oocyte functional studies
Sources: Literature
Congenital Heart Defect v0.82 PRKACB Zornitza Stark Phenotypes for gene: PRKACB were changed from Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability to Cardioacrofacial dysplasia 2, MIM# 619143; Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability
Congenital Heart Defect v0.81 PRKACB Zornitza Stark reviewed gene: PRKACB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardioacrofacial dysplasia 2, MIM# 619143; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.81 PRKACA Zornitza Stark Phenotypes for gene: PRKACA were changed from Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability to Cardioacrofacial dysplasia 1, MIM# 619142; Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability
Congenital Heart Defect v0.80 PRKACA Zornitza Stark reviewed gene: PRKACA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardioacrofacial dysplasia 1, MIM# 619142; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.80 PRKACA Zornitza Stark Marked gene: PRKACA as ready
Congenital Heart Defect v0.80 PRKACA Zornitza Stark Gene: prkaca has been classified as Green List (High Evidence).
Congenital Heart Defect v0.80 PRKACA Zornitza Stark Classified gene: PRKACA as Green List (high evidence)
Congenital Heart Defect v0.80 PRKACA Zornitza Stark Gene: prkaca has been classified as Green List (High Evidence).
Congenital Heart Defect v0.79 PRKACB Zornitza Stark Marked gene: PRKACB as ready
Congenital Heart Defect v0.79 PRKACB Zornitza Stark Gene: prkacb has been classified as Green List (High Evidence).
Congenital Heart Defect v0.79 PRKACB Zornitza Stark Classified gene: PRKACB as Green List (high evidence)
Congenital Heart Defect v0.79 PRKACB Zornitza Stark Gene: prkacb has been classified as Green List (High Evidence).
Congenital Heart Defect v0.78 PRKACA Konstantinos Varvagiannis gene: PRKACA was added
gene: PRKACA was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: PRKACA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKACA were set to 33058759; 31130284
Phenotypes for gene: PRKACA were set to Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability
Penetrance for gene: PRKACA were set to unknown
Mode of pathogenicity for gene: PRKACA was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: PRKACA was set to GREEN
Added comment: Palencia-Campos et al (2020 - PMID: 33058759) report on the phenotype of 3 individuals heterozygous for PRKACA and 4 individuals heterozygous for PRKACB pathogenic variants.

The most characteristic features in all individuals with PRKACA/PRKACB mutation, included postaxial polydactyly of hands (6/7 bilateral, 1/7 unilateral) and feet (4/7 bilateral, 1/7 unilateral), brachydactyly and congenital heart defects (CHD 5/7) namely a common atrium or AVSD. Two individuals with PRKACA variant who did not have CHD had offspring with the same variant and an AVSD.

Other variably occurring features included short stature, limbs, narrow chest, abnormal teeth, oral frenula, nail dysplasia. One individual with PRKACB variant presented tumors.

Intellectual disability was reported in 2/4 individuals with PRKACB variant (1/4: mild, 1/4: severe). The 3 individuals with PRKACA variant did not present ID.

As the phenotype was overall suggestive of Ellis-van Creveld syndrome (or the allelic Weyers acrofacial dysostosis), although these diagnoses were ruled out following analysis of EVC and EVC2 genes.

WES was carried out in all.

PRKACA : A single heterozygous missense variant was identified in 3 individuals from 3 families (NM_002730.4:c.409G>A / p.Gly137Arg) with 1 of the probands harboring the variant in mosaic state (28% of reads) and having 2 similarly affected offspring. The variant was de novo in one individual and inherited in a third one having a similarly affected fetus (narrow thorax, postaxial polyd, AVSD).

PRKACB : 4 different variants were identified (NM_002731.3: p.His88Arg/Asn, p.Gly235Arg, c.161C>T - p.Ser54Leu). One of the individuals was mosaic for the latter variant, while in all other cases the variant had occurred de novo.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes.

The authors provide evidence that the variants confer increased sensitivity of PKA holoenzymes to activation by cAMP (compared to wt).

By performing ectopic expression of wt or mt PRKACA/B (variants studied : PRKACA p.Gly137Arg / PRKACB p.Gly235Arg) in NIH 3T3 fibroblasts, the authors demonstrate that inhibition of hedgehog signaling likely underlyies the developmental defects observed in affected individuals.

As for PRKACA, the authors cite another study where a 31-month old female with EvC syndrome diagnosis was found to harbor the aforementioned variant (NM_001304349.1:c.637G>A:p.Gly213Arg corresponding to NM_002730.4:c.409G>A / p.Gly137Arg) as a de novo event. Without additional evidence at the time, the variant was considered to be a candidate for this subject's phenotype (Monies et al 2019 – PMID: 31130284).
Sources: Literature
Congenital Heart Defect v0.78 PRKACB Konstantinos Varvagiannis gene: PRKACB was added
gene: PRKACB was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: PRKACB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRKACB were set to 33058759
Phenotypes for gene: PRKACB were set to Postaxial hand polydactyly; Postaxial foot polydactyly; Common atrium; Atrioventricular canal defect; Narrow chest; Abnormality of the teeth; Intellectual disability
Penetrance for gene: PRKACB were set to Complete
Mode of pathogenicity for gene: PRKACB was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: PRKACB was set to GREEN
Added comment: Palencia-Campos et al (2020 - PMID: 33058759) report on the phenotype of 3 individuals heterozygous for PRKACA and 4 individuals heterozygous for PRKACB pathogenic variants.

The most characteristic features in all individuals with PRKACA/PRKACB mutation, included postaxial polydactyly of hands (6/7 bilateral, 1/7 unilateral) and feet (4/7 bilateral, 1/7 unilateral), brachydactyly and congenital heart defects (CHD 5/7) namely a common atrium or AVSD. Two individuals with PRKACA variant who did not have CHD had offspring with the same variant and an AVSD.

Other variably occurring features included short stature, limbs, narrow chest, abnormal teeth, oral frenula, nail dysplasia. One individual with PRKACB variant presented tumors.

Intellectual disability was reported in 2/4 individuals with PRKACB variant (1/4: mild, 1/4: severe). The 3 individuals with PRKACA variant did not present ID.

As the phenotype was overall suggestive of Ellis-van Creveld syndrome (or the allelic Weyers acrofacial dysostosis), although these diagnoses were ruled out following analysis of EVC and EVC2 genes.

WES was carried out in all.

PRKACA : A single heterozygous missense variant was identified in 3 individuals from 3 families (NM_002730.4:c.409G>A / p.Gly137Arg) with 1 of the probands harboring the variant in mosaic state (28% of reads) and having 2 similarly affected offspring. The variant was de novo in one individual and inherited in a third one having a similarly affected fetus (narrow thorax, postaxial polyd, AVSD).

PRKACB : 4 different variants were identified (NM_002731.3: p.His88Arg/Asn, p.Gly235Arg, c.161C>T - p.Ser54Leu). One of the individuals was mosaic for the latter variant, while in all other cases the variant had occurred de novo.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes.

The authors provide evidence that the variants confer increased sensitivity of PKA holoenzymes to activation by cAMP (compared to wt).

By performing ectopic expression of wt or mt PRKACA/B (variants studied : PRKACA p.Gly137Arg / PRKACB p.Gly235Arg) in NIH 3T3 fibroblasts, the authors demonstrate that inhibition of hedgehog signaling likely underlyies the developmental defects observed in affected individuals.

As for PRKACA, the authors cite another study where a 31-month old female with EvC syndrome diagnosis was found to harbor the aforementioned variant (NM_001304349.1:c.637G>A:p.Gly213Arg corresponding to NM_002730.4:c.409G>A / p.Gly137Arg) as a de novo event. Without additional evidence at the time, the variant was considered to be a candidate for this subject's phenotype (Monies et al 2019 – PMID: 31130284).
Sources: Literature
Congenital Heart Defect v0.78 KANSL1 Zornitza Stark Tag SV/CNV tag was added to gene: KANSL1.
Congenital Heart Defect v0.78 KANSL1 Zornitza Stark Marked gene: KANSL1 as ready
Congenital Heart Defect v0.78 KANSL1 Zornitza Stark Gene: kansl1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.78 KANSL1 Zornitza Stark Phenotypes for gene: KANSL1 were changed from to Koolen-De Vries syndrome, MIM# 610443
Congenital Heart Defect v0.77 KANSL1 Zornitza Stark Publications for gene: KANSL1 were set to
Congenital Heart Defect v0.76 KANSL1 Zornitza Stark Mode of inheritance for gene: KANSL1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.75 KANSL1 Zornitza Stark reviewed gene: KANSL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26306646; Phenotypes: Koolen-De Vries syndrome, MIM# 610443; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.75 TAF1 Zornitza Stark Marked gene: TAF1 as ready
Congenital Heart Defect v0.75 TAF1 Zornitza Stark Gene: taf1 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.75 TAF1 Zornitza Stark Phenotypes for gene: TAF1 were changed from Dystonia-Parkinsonism, X-linked 314250; Mental retardation, X-linked, syndromic 33 300966; congenital cardiac disease and global developmental delay to Mental retardation, X-linked, syndromic 33 300966; congenital cardiac disease and global developmental delay
Congenital Heart Defect v0.74 TAF1 Zornitza Stark Classified gene: TAF1 as Amber List (moderate evidence)
Congenital Heart Defect v0.74 TAF1 Zornitza Stark Gene: taf1 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.73 TAF1 Elena Savva gene: TAF1 was added
gene: TAF1 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: TAF1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: TAF1 were set to PMID: 32396742; 31646703; 26637982; 31341187
Phenotypes for gene: TAF1 were set to Dystonia-Parkinsonism, X-linked 314250; Mental retardation, X-linked, syndromic 33 300966; congenital cardiac disease and global developmental delay
Review for gene: TAF1 was set to AMBER
Added comment: -Carrier females consistently shown to be asymptomatic with skewed X-inactivation
-While no PTCs have been reported, the lack of representation in population databases strongly suggests these mutations are not compatible with life (Gudmundsson, S. et al. (2019))

Two patients with hemizygous missense variants, with congenital cardiac disease and global developmental delay
Sources: Literature
Congenital Heart Defect v0.73 ACTC1 Zornitza Stark Marked gene: ACTC1 as ready
Congenital Heart Defect v0.73 ACTC1 Zornitza Stark Gene: actc1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.73 ACTC1 Zornitza Stark Phenotypes for gene: ACTC1 were changed from to Atrial septal defect 5, MIM# 612794
Congenital Heart Defect v0.72 ACTC1 Zornitza Stark Publications for gene: ACTC1 were set to
Congenital Heart Defect v0.71 ACTC1 Zornitza Stark Mode of inheritance for gene: ACTC1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.70 ACTC1 Zornitza Stark reviewed gene: ACTC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17947298, 31430208; Phenotypes: Atrial septal defect 5, MIM# 612794; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.70 PRKD1 Zornitza Stark changed review comment from: PMID: 32817298 (2020) - Two additional unrelated cases with de novo variants, c.1774G>C and c.1808G>A, and telangiectasia, ectodermal dysplasia, brachydactyly and congenital heart disease. Functional analysis using in vitro kinase assays with recombinant proteins showed that the c.1808G>A, p.(Arg603His) variant represents a gain-of-function mutation encoding an enzyme with a constitutive, lipid-independent catalytic activity. The c.1774G>C, p.(Gly592Arg) variant in contrast shows a defect in substrate phosphorylation representing a loss-of-function mutation.

c.1774G>C, p.(Gly592Arg) is recurrent, reported in 3/5 individuals.; to: PMID: 27479907 (2016): three individuals reported, two with the c.1774G>A variant and one with the c.896T>G variant. All had congenital heart disease, two had some developmental delay, and two had variable features of ectodermal dysplasia, including sparse hair, dry skin, thin skin, fragile nails, premature loss of primary teeth, and small widely spaced teeth; the third individuals had a 'disorganized eyebrow.'

PMID: 32817298 (2020) - Two additional unrelated cases with de novo variants, c.1774G>C and c.1808G>A, and telangiectasia, ectodermal dysplasia, brachydactyly and congenital heart disease. Functional analysis using in vitro kinase assays with recombinant proteins showed that the c.1808G>A, p.(Arg603His) variant represents a gain-of-function mutation encoding an enzyme with a constitutive, lipid-independent catalytic activity. The c.1774G>C, p.(Gly592Arg) variant in contrast shows a defect in substrate phosphorylation representing a loss-of-function mutation.

c.1774G>C, p.(Gly592Arg) is recurrent, reported in 3/5 individuals.
Congenital Heart Defect v0.70 PRKD1 Zornitza Stark Publications for gene: PRKD1 were set to 27479907
Congenital Heart Defect v0.70 PRKD1 Zornitza Stark Mode of pathogenicity for gene: PRKD1 was changed from to Other
Congenital Heart Defect v0.69 PRKD1 Zornitza Stark edited their review of gene: PRKD1: Added comment: PMID: 32817298 (2020) - Two additional unrelated cases with de novo variants, c.1774G>C and c.1808G>A, and telangiectasia, ectodermal dysplasia, brachydactyly and congenital heart disease. Functional analysis using in vitro kinase assays with recombinant proteins showed that the c.1808G>A, p.(Arg603His) variant represents a gain-of-function mutation encoding an enzyme with a constitutive, lipid-independent catalytic activity. The c.1774G>C, p.(Gly592Arg) variant in contrast shows a defect in substrate phosphorylation representing a loss-of-function mutation.

c.1774G>C, p.(Gly592Arg) is recurrent, reported in 3/5 individuals.; Changed publications: 27479907, 32817298
Congenital Heart Defect v0.69 SHOC2 Zornitza Stark Marked gene: SHOC2 as ready
Congenital Heart Defect v0.69 SHOC2 Zornitza Stark Gene: shoc2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.69 SHOC2 Zornitza Stark Phenotypes for gene: SHOC2 were changed from to Noonan syndrome-like with loose anagen hair 1, MIM# 607721
Congenital Heart Defect v0.68 SHOC2 Zornitza Stark Publications for gene: SHOC2 were set to
Congenital Heart Defect v0.67 SHOC2 Zornitza Stark Mode of inheritance for gene: SHOC2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.66 SHOC2 Zornitza Stark reviewed gene: SHOC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19684605, 23918763, 20882035; Phenotypes: Noonan syndrome-like with loose anagen hair 1, MIM# 607721; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.66 HSPA9 Zornitza Stark Marked gene: HSPA9 as ready
Congenital Heart Defect v0.66 HSPA9 Zornitza Stark Gene: hspa9 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.66 HSPA9 Zornitza Stark Phenotypes for gene: HSPA9 were changed from https://www.omim.org/entry/616854; skeletal anomalies; congenital cardiac and renal anomalies: marked small nose to Even-plus syndrome, MIM# 616854; skeletal anomalies; congenital cardiac and renal anomalies: marked small nose
Congenital Heart Defect v0.65 HSPA9 Zornitza Stark Classified gene: HSPA9 as Green List (high evidence)
Congenital Heart Defect v0.65 HSPA9 Zornitza Stark Gene: hspa9 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.62 HSPA9 Sue White gene: HSPA9 was added
gene: HSPA9 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: HSPA9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HSPA9 were set to 26598328; 32869452
Phenotypes for gene: HSPA9 were set to https://www.omim.org/entry/616854; skeletal anomalies; congenital cardiac and renal anomalies: marked small nose
Review for gene: HSPA9 was set to GREEN
Added comment: Biallelic variants in 4 individuals from 5 families. Significant skeletal features and marked nasal hypoplasia with mid-face hypoplasia.
2/5 with developmental delay and abnormalities of the corpus callosum
4/5 with congenital heart disease
Sources: Literature
Congenital Heart Defect v0.62 HSPA9 Sue White gene: HSPA9 was added
gene: HSPA9 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: HSPA9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HSPA9 were set to 26598328; 32869452
Phenotypes for gene: HSPA9 were set to https://www.omim.org/entry/616854; skeletal anomalies; congenital cardiac and renal anomalies: marked small nose
Review for gene: HSPA9 was set to GREEN
Added comment: Biallelic variants in 4 individuals from 5 families. Significant skeletal features and marked nasal hypoplasia with mid-face hypoplasia.
2/5 with developmental delay and abnormalities of the corpus callosum
4/5 with congenital heart disease
Sources: Literature
Congenital Heart Defect v0.61 TBX1 Zornitza Stark Marked gene: TBX1 as ready
Congenital Heart Defect v0.61 TBX1 Zornitza Stark Gene: tbx1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.61 TBX1 Zornitza Stark Phenotypes for gene: TBX1 were changed from to DiGeorge syndrome (MIM#188400)
Congenital Heart Defect v0.60 TBX1 Zornitza Stark Mode of pathogenicity for gene: TBX1 was changed from None to None
Congenital Heart Defect v0.59 TBX1 Zornitza Stark Publications for gene: TBX1 were set to
Congenital Heart Defect v0.58 TBX1 Zornitza Stark Mode of pathogenicity for gene: TBX1 was changed from to None
Congenital Heart Defect v0.57 TBX1 Zornitza Stark Mode of inheritance for gene: TBX1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.56 TBX1 Crystle Lee edited their review of gene: TBX1: Changed rating: GREEN
Congenital Heart Defect v0.56 TBX1 Crystle Lee reviewed gene: TBX1: Rating: AMBER; Mode of pathogenicity: Other; Publications: 31428446, 32110744, 29250159, 30137364, 24998776, 28272434; Phenotypes: DiGeorge syndrome (MIM#188400); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital Heart Defect v0.56 SMO Zornitza Stark Phenotypes for gene: SMO were changed from Microcephaly, congenital heart disease, polydactyly, aganglionosis to Microcephaly, congenital heart disease, polydactyly, aganglionosis; Pallister-Hall-like syndrome , MIM#241800
Congenital Heart Defect v0.55 SMO Zornitza Stark edited their review of gene: SMO: Changed phenotypes: Microcephaly, congenital heart disease, polydactyly, aganglionosis, Pallister-Hall-like syndrome , MIM#241800
Congenital Heart Defect v0.55 BCOR Zornitza Stark Marked gene: BCOR as ready
Congenital Heart Defect v0.55 BCOR Zornitza Stark Gene: bcor has been classified as Green List (High Evidence).
Congenital Heart Defect v0.55 BCOR Zornitza Stark Phenotypes for gene: BCOR were changed from to Microphthalmia, syndromic 2, MIM# 300166; Oculofaciocardiodental syndrome; Lenz microphthalmia
Congenital Heart Defect v0.54 BCOR Zornitza Stark Publications for gene: BCOR were set to
Congenital Heart Defect v0.53 BCOR Zornitza Stark Mode of inheritance for gene: BCOR was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Congenital Heart Defect v0.52 BCOR Zornitza Stark reviewed gene: BCOR: Rating: GREEN; Mode of pathogenicity: None; Publications: 29974297; Phenotypes: Microphthalmia, syndromic 2, MIM# 300166, Oculofaciocardiodental syndrome, Lenz microphthalmia; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Congenital Heart Defect v0.52 TMEM94 Zornitza Stark Marked gene: TMEM94 as ready
Congenital Heart Defect v0.52 TMEM94 Zornitza Stark Gene: tmem94 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.52 TMEM94 Zornitza Stark Classified gene: TMEM94 as Green List (high evidence)
Congenital Heart Defect v0.52 TMEM94 Zornitza Stark Gene: tmem94 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.51 TMEM94 Zornitza Stark gene: TMEM94 was added
gene: TMEM94 was added to Congenital Heart Defect. Sources: Expert list
Mode of inheritance for gene: TMEM94 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM94 were set to Intellectual developmental disorder with cardiac defects and dysmorphic facies
Phenotypes for gene: TMEM94 were set to 30526868
Review for gene: TMEM94 was set to GREEN
Added comment: Ten individuals from 6 unrelated families reported, variety of congenital heart defects in addition to ID (ASD, VSD, Tetralogy of Fallot).
Sources: Expert list
Congenital Heart Defect v0.50 ADAMTS19 Chirag Patel Classified gene: ADAMTS19 as Green List (high evidence)
Congenital Heart Defect v0.50 ADAMTS19 Chirag Patel Gene: adamts19 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.49 ADAMTS19 Chirag Patel reviewed gene: ADAMTS19: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32323311, 31844321; Phenotypes: Heart valve disease (HVD); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.49 ABL1 Zornitza Stark Marked gene: ABL1 as ready
Congenital Heart Defect v0.49 ABL1 Zornitza Stark Gene: abl1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.49 ABL1 Zornitza Stark Classified gene: ABL1 as Green List (high evidence)
Congenital Heart Defect v0.49 ABL1 Zornitza Stark Gene: abl1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.48 ABL1 Ain Roesley gene: ABL1 was added
gene: ABL1 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: ABL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ABL1 were set to PMID: 28288113
Phenotypes for gene: ABL1 were set to Congenital heart defects and skeletal malformations syndrome (MIM# 617602)
Penetrance for gene: ABL1 were set to unknown
Review for gene: ABL1 was set to GREEN
Added comment: PMID: 28288113: six affected individuals from 4 unrelated families who shared similar clinical features including dysmorphic facial features (6/6), congenital heart disease (CHD, 6/6), skeletal abnormalities (6/6), joint problems (5/6), failure to thrive (5/6), gastrointestinal problems (5/6), and male genital/sexual abnormalities (3/4). Missense variants with 3 families sharing the same variant (Tyr245Cys).
Authors also noted similar congenital malformations observed in fetuses exposed to the selective tyrosine kinase inhibitor imatinib, and patients with constitutional ABL1 variants
Sources: Literature
Congenital Heart Defect v0.48 SMO Zornitza Stark Marked gene: SMO as ready
Congenital Heart Defect v0.48 SMO Zornitza Stark Gene: smo has been classified as Green List (High Evidence).
Congenital Heart Defect v0.48 SMO Zornitza Stark Classified gene: SMO as Green List (high evidence)
Congenital Heart Defect v0.48 SMO Zornitza Stark Gene: smo has been classified as Green List (High Evidence).
Congenital Heart Defect v0.47 SMO Zornitza Stark gene: SMO was added
gene: SMO was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: SMO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMO were set to 32413283
Phenotypes for gene: SMO were set to Microcephaly, congenital heart disease, polydactyly, aganglionosis
Review for gene: SMO was set to GREEN
Added comment: Bi-allelic loss-of-function variations in SMO reported in seven individuals from five independent families. Wide phenotypic spectrum of developmental anomalies affecting the brain (hypothalamic hamartoma and microcephaly), heart (atrioventricular septal defect), skeleton (postaxial polydactyly, narrow chest, and shortening of long bones), and enteric nervous system (aganglionosis).
Sources: Literature
Congenital Heart Defect v0.46 Zornitza Stark Panel types changed to Victorian Clinical Genetics Services; Rare Disease
Congenital Heart Defect v0.45 NKX2-5 Zornitza Stark Marked gene: NKX2-5 as ready
Congenital Heart Defect v0.45 NKX2-5 Zornitza Stark Gene: nkx2-5 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.45 NKX2-5 Zornitza Stark Phenotypes for gene: NKX2-5 were changed from to Ventricular septal defect 3 (MIM#614432); Tetralogy of Fallot (MIM#187500)
Congenital Heart Defect v0.44 NKX2-5 Zornitza Stark Publications for gene: NKX2-5 were set to
Congenital Heart Defect v0.43 NKX2-5 Zornitza Stark Mode of inheritance for gene: NKX2-5 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.43 NKX2-5 Zornitza Stark Mode of inheritance for gene: NKX2-5 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.42 TLL1 Zornitza Stark Marked gene: TLL1 as ready
Congenital Heart Defect v0.42 TLL1 Zornitza Stark Gene: tll1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.42 TLL1 Zornitza Stark Publications for gene: TLL1 were set to
Congenital Heart Defect v0.41 TLL1 Zornitza Stark Mode of inheritance for gene: TLL1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.40 TLL1 Zornitza Stark reviewed gene: TLL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18830233, 30538173, 27418595, 31570783; Phenotypes: Atrial septal defect; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.40 MYH6 Crystle Lee reviewed gene: MYH6: Rating: GREEN; Mode of pathogenicity: Other; Publications: 20656787, 29969989, 15735645; Phenotypes: Atrial septal defect 3 (MIM#614089); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital Heart Defect v0.40 NKX2-5 Crystle Lee reviewed gene: NKX2-5: Rating: GREEN; Mode of pathogenicity: None; Publications: 25742962, 26805889; Phenotypes: Ventricular septal defect 3 (MIM#614432), Tetralogy of Fallot (MIM#187500); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital Heart Defect v0.40 PRKD1 Zornitza Stark Marked gene: PRKD1 as ready
Congenital Heart Defect v0.40 PRKD1 Zornitza Stark Gene: prkd1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.40 PRKD1 Zornitza Stark Phenotypes for gene: PRKD1 were changed from to Congenital heart defects and ectodermal dysplasia, 617364
Congenital Heart Defect v0.39 PRKD1 Zornitza Stark Publications for gene: PRKD1 were set to
Congenital Heart Defect v0.38 PRKD1 Zornitza Stark Mode of inheritance for gene: PRKD1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.37 PRKD1 Zornitza Stark reviewed gene: PRKD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27479907; Phenotypes: Congenital heart defects and ectodermal dysplasia, 617364; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.37 NODAL Zornitza Stark Tag disputed tag was added to gene: NODAL.
Congenital Heart Defect v0.37 NODAL Zornitza Stark Marked gene: NODAL as ready
Congenital Heart Defect v0.37 NODAL Zornitza Stark Gene: nodal has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.37 NODAL Zornitza Stark Phenotypes for gene: NODAL were changed from to Heterotaxy, visceral, 5 (MIM#270100)
Congenital Heart Defect v0.36 NODAL Zornitza Stark Publications for gene: NODAL were set to
Congenital Heart Defect v0.35 NODAL Zornitza Stark Mode of inheritance for gene: NODAL was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.34 NODAL Zornitza Stark Classified gene: NODAL as Red List (low evidence)
Congenital Heart Defect v0.34 NODAL Zornitza Stark Gene: nodal has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.33 NODAL Zornitza Stark reviewed gene: NODAL: Rating: RED; Mode of pathogenicity: None; Publications: 9354794, 19064609; Phenotypes: Heterotaxy, visceral, 5 (MIM#270100); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.33 ACVR2B Zornitza Stark Phenotypes for gene: ACVR2B were changed from to Heterotaxy, visceral, 4, autosomal 613751
Congenital Heart Defect v0.32 ACVR2B Zornitza Stark Publications for gene: ACVR2B were set to
Congenital Heart Defect v0.31 ACVR2B Zornitza Stark Mode of inheritance for gene: ACVR2B was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.30 ACVR2B Zornitza Stark Classified gene: ACVR2B as Red List (low evidence)
Congenital Heart Defect v0.30 ACVR2B Zornitza Stark Gene: acvr2b has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.29 ACVR2B Zornitza Stark reviewed gene: ACVR2B: Rating: RED; Mode of pathogenicity: None; Publications: 9916847, 30622330, 21864452; Phenotypes: Heterotaxy, visceral, 4, autosomal 613751; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.29 ADAMTS19 Zornitza Stark Marked gene: ADAMTS19 as ready
Congenital Heart Defect v0.29 ADAMTS19 Zornitza Stark Gene: adamts19 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.29 ADAMTS19 Zornitza Stark Classified gene: ADAMTS19 as Amber List (moderate evidence)
Congenital Heart Defect v0.29 ADAMTS19 Zornitza Stark Gene: adamts19 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.28 ADAMTS19 Zornitza Stark gene: ADAMTS19 was added
gene: ADAMTS19 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: ADAMTS19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAMTS19 were set to 31844321
Phenotypes for gene: ADAMTS19 were set to Non-syndromic heart valve disease
Review for gene: ADAMTS19 was set to AMBER
Added comment: PMID: 31844321; Wünnemann 2020: 4 affected in 2 unrelated consanguineous families with non-syndromic heart valve disease. 1 family with an intragenic (exon 1-8) deletion and 1 nonsense variant. Carriers unaffected. Homozygous knockout mice for Adamts19 show aortic valve dysfunction, recapitulating aspects of the human phenotype
Sources: Literature
Congenital Heart Defect v0.27 TLL1 Bryony Thompson reviewed gene: TLL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27418595, 30538173, 31570783, 18830233, 10331975; Phenotypes: Atrial septal defect 6 MIM#613087; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.27 TMEM260 Zornitza Stark Marked gene: TMEM260 as ready
Congenital Heart Defect v0.27 TMEM260 Zornitza Stark Gene: tmem260 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.27 TMEM260 Zornitza Stark Classified gene: TMEM260 as Amber List (moderate evidence)
Congenital Heart Defect v0.27 TMEM260 Zornitza Stark Gene: tmem260 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.26 TMEM260 Zornitza Stark gene: TMEM260 was added
gene: TMEM260 was added to Congenital Heart Defect. Sources: Expert list
Mode of inheritance for gene: TMEM260 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM260 were set to 28318500
Phenotypes for gene: TMEM260 were set to Structural heart defects and renal anomalies syndrome, MIM# 617478
Review for gene: TMEM260 was set to AMBER
Added comment: Two unrelated families with complex severe congenital heart disease.
Sources: Expert list
Congenital Heart Defect v0.25 CDK13 Zornitza Stark Marked gene: CDK13 as ready
Congenital Heart Defect v0.25 CDK13 Zornitza Stark Gene: cdk13 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.25 CDK13 Zornitza Stark Phenotypes for gene: CDK13 were changed from to Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder, 617360
Congenital Heart Defect v0.24 CDK13 Zornitza Stark Publications for gene: CDK13 were set to
Congenital Heart Defect v0.23 CDK13 Zornitza Stark Mode of inheritance for gene: CDK13 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.22 CDK13 Kristin Rigbye reviewed gene: CDK13: Rating: GREEN; Mode of pathogenicity: None; Publications: 29021403, 29393965, 30904094; Phenotypes: Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder, 617360; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.22 FLT4 Zornitza Stark Marked gene: FLT4 as ready
Congenital Heart Defect v0.22 FLT4 Zornitza Stark Gene: flt4 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.22 FLT4 Zornitza Stark Phenotypes for gene: FLT4 were changed from to Congenital heart defects, multiple types, 7, MIM#618780
Congenital Heart Defect v0.21 FLT4 Zornitza Stark Publications for gene: FLT4 were set to
Congenital Heart Defect v0.20 FLT4 Zornitza Stark Mode of inheritance for gene: FLT4 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.19 CITED2 Zornitza Stark Marked gene: CITED2 as ready
Congenital Heart Defect v0.19 CITED2 Zornitza Stark Added comment: Comment when marking as ready: Supportive animal model data.
Congenital Heart Defect v0.19 CITED2 Zornitza Stark Gene: cited2 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.19 CITED2 Zornitza Stark Phenotypes for gene: CITED2 were changed from to Atrial septal defect 8, 614433; Ventricular septal defect 2, 614431
Congenital Heart Defect v0.18 CITED2 Zornitza Stark Publications for gene: CITED2 were set to
Congenital Heart Defect v0.18 CITED2 Zornitza Stark Mode of inheritance for gene: CITED2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.17 FLT4 Tegan French reviewed gene: FLT4: Rating: GREEN; Mode of pathogenicity: None; Publications: PubMed: 30232381; Phenotypes: Congenital heart defects, multiple types, 7; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.17 CITED2 Kristin Rigbye reviewed gene: CITED2: Rating: GREEN; Mode of pathogenicity: None; Publications: 16287139; Phenotypes: Atrial septal defect 8, 614433, Ventricular septal defect 2, 614431; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.17 TBX3 Zornitza Stark Marked gene: TBX3 as ready
Congenital Heart Defect v0.17 TBX3 Zornitza Stark Gene: tbx3 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.17 TBX3 Zornitza Stark Classified gene: TBX3 as Green List (high evidence)
Congenital Heart Defect v0.17 TBX3 Zornitza Stark Gene: tbx3 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.16 TBX3 Zornitza Stark gene: TBX3 was added
gene: TBX3 was added to Congenital Heart Defect. Sources: Expert list
Mode of inheritance for gene: TBX3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TBX3 were set to Ulnar-mammary syndrome, MIM# 181450
Review for gene: TBX3 was set to GREEN
Added comment: VSD and WPW described.
Sources: Expert list
Congenital Heart Defect v0.15 TBX2 Zornitza Stark Marked gene: TBX2 as ready
Congenital Heart Defect v0.15 TBX2 Zornitza Stark Gene: tbx2 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.15 TBX2 Zornitza Stark Classified gene: TBX2 as Amber List (moderate evidence)
Congenital Heart Defect v0.15 TBX2 Zornitza Stark Gene: tbx2 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.14 TBX2 Zornitza Stark gene: TBX2 was added
gene: TBX2 was added to Congenital Heart Defect. Sources: Expert list
Mode of inheritance for gene: TBX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TBX2 were set to 29726930
Phenotypes for gene: TBX2 were set to Vertebral anomalies and variable endocrine and T-cell dysfunction, MIM# 618223
Review for gene: TBX2 was set to AMBER
Added comment: Two families reported; congenital heart disease is part of the phenotype.
Sources: Expert list
Congenital Heart Defect v0.13 ROBO1 Zornitza Stark Marked gene: ROBO1 as ready
Congenital Heart Defect v0.13 ROBO1 Zornitza Stark Gene: robo1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.13 ROBO1 Zornitza Stark Classified gene: ROBO1 as Green List (high evidence)
Congenital Heart Defect v0.13 ROBO1 Zornitza Stark Gene: robo1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.12 ROBO1 Zornitza Stark gene: ROBO1 was added
gene: ROBO1 was added to Congenital Heart Defect. Sources: Expert list
Mode of inheritance for gene: ROBO1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ROBO1 were set to 28592524
Phenotypes for gene: ROBO1 were set to Tetralogy of Fallot; septal defects
Review for gene: ROBO1 was set to GREEN
Added comment: Three families reported and a mouse model. Note mono allelic and bi-allelic variants in this gene also linked with pituitary abnormalities.
Sources: Expert list
Congenital Heart Defect v0.11 PLD1 Zornitza Stark Marked gene: PLD1 as ready
Congenital Heart Defect v0.11 PLD1 Zornitza Stark Gene: pld1 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.11 PLD1 Zornitza Stark Classified gene: PLD1 as Amber List (moderate evidence)
Congenital Heart Defect v0.11 PLD1 Zornitza Stark Gene: pld1 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.10 PLD1 Zornitza Stark gene: PLD1 was added
gene: PLD1 was added to Congenital Heart Defect. Sources: Expert list
Mode of inheritance for gene: PLD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLD1 were set to 27799408
Phenotypes for gene: PLD1 were set to Cardiac valvular defect, developmental, MIM# 212093
Review for gene: PLD1 was set to AMBER
Added comment: Four individuals from two families reported.
Sources: Expert list
Congenital Heart Defect v0.9 NONO Zornitza Stark Marked gene: NONO as ready
Congenital Heart Defect v0.9 NONO Zornitza Stark Gene: nono has been classified as Green List (High Evidence).
Congenital Heart Defect v0.9 NONO Zornitza Stark Classified gene: NONO as Green List (high evidence)
Congenital Heart Defect v0.9 NONO Zornitza Stark Gene: nono has been classified as Green List (High Evidence).
Congenital Heart Defect v0.8 NONO Zornitza Stark gene: NONO was added
gene: NONO was added to Congenital Heart Defect. Sources: Expert list
Mode of inheritance for gene: NONO was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: NONO were set to 26571461; 27329731; 27550220
Phenotypes for gene: NONO were set to Mental retardation, X-linked, syndromic 34, MIM# 300967
Review for gene: NONO was set to GREEN
Added comment: Structural heart defects and cardiomyopathy are features of this syndromic disorder.
Sources: Expert list
Congenital Heart Defect v0.7 MYOCD Zornitza Stark Marked gene: MYOCD as ready
Congenital Heart Defect v0.7 MYOCD Zornitza Stark Gene: myocd has been classified as Green List (High Evidence).
Congenital Heart Defect v0.7 MYOCD Zornitza Stark Classified gene: MYOCD as Green List (high evidence)
Congenital Heart Defect v0.7 MYOCD Zornitza Stark Gene: myocd has been classified as Green List (High Evidence).
Congenital Heart Defect v0.6 MYOCD Zornitza Stark gene: MYOCD was added
gene: MYOCD was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: MYOCD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYOCD were set to 31513549
Phenotypes for gene: MYOCD were set to Megabladder; congenital heart disease; cardiomyopathy
Review for gene: MYOCD was set to GREEN
Added comment: Four unrelated families. Mono allelic disease in males (megabladder), bi-allelic disease in males and females (megabladder and congenital heart disease).
Sources: Literature
Congenital Heart Defect v0.5 Zornitza Stark Panel name changed from Congenital Heart Defect_VCGS to Congenital Heart Defect
Panel types changed to Victorian Clinical Genetics Services
Congenital Heart Defect v0.4 MEF2C Zornitza Stark Marked gene: MEF2C as ready
Congenital Heart Defect v0.4 MEF2C Zornitza Stark Gene: mef2c has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.4 MEF2C Zornitza Stark gene: MEF2C was added
gene: MEF2C was added to Congenital Heart Defect_VCGS. Sources: Expert list
Mode of inheritance for gene: MEF2C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MEF2C were set to 29104469; 22498567; 26811383
Phenotypes for gene: MEF2C were set to Congenital heart disease
Review for gene: MEF2C was set to RED
Added comment: Two families described and an animal model. This is very low level of evidence considering the prevalence of CHD.
Sources: Expert list
Congenital Heart Defect v0.3 IRX4 Zornitza Stark Marked gene: IRX4 as ready
Congenital Heart Defect v0.3 IRX4 Zornitza Stark Gene: irx4 has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.3 IRX4 Zornitza Stark gene: IRX4 was added
gene: IRX4 was added to Congenital Heart Defect_VCGS. Sources: Expert list
Mode of inheritance for gene: IRX4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IRX4 were set to 21544582
Phenotypes for gene: IRX4 were set to Ventricular septal defect
Review for gene: IRX4 was set to RED
Added comment: Two individuals with novel missense variants identified in a large cohort in 2011.
Sources: Expert list
Congenital Heart Defect v0.2 ROBO4 Zornitza Stark Marked gene: ROBO4 as ready
Congenital Heart Defect v0.2 ROBO4 Zornitza Stark Added comment: Comment when marking as ready: Two families, functional data.
Congenital Heart Defect v0.2 ROBO4 Zornitza Stark Gene: robo4 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.2 ROBO4 Zornitza Stark Classified gene: ROBO4 as Green List (high evidence)
Congenital Heart Defect v0.2 ROBO4 Zornitza Stark Gene: robo4 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.1 ROBO4 Sue White gene: ROBO4 was added
gene: ROBO4 was added to Congenital Heart Defect_VCGS. Sources: Literature
Mode of inheritance for gene: ROBO4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ROBO4 were set to 30455415
Phenotypes for gene: ROBO4 were set to bicuspid aortic valve; ascending aortic aneurysm; ascending aorta dilatation
Penetrance for gene: ROBO4 were set to Incomplete
Review for gene: ROBO4 was set to GREEN
Added comment: incomplete penetrance
Sources: Literature
Congenital Heart Defect v0.0 ZIC3 Zornitza Stark gene: ZIC3 was added
gene: ZIC3 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: ZIC3 was set to Unknown
Congenital Heart Defect v0.0 ZFPM2 Zornitza Stark gene: ZFPM2 was added
gene: ZFPM2 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: ZFPM2 was set to Unknown
Congenital Heart Defect v0.0 ZEB2 Zornitza Stark gene: ZEB2 was added
gene: ZEB2 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: ZEB2 was set to Unknown
Congenital Heart Defect v0.0 UBR1 Zornitza Stark gene: UBR1 was added
gene: UBR1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: UBR1 was set to Unknown
Congenital Heart Defect v0.0 TLL1 Zornitza Stark gene: TLL1 was added
gene: TLL1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: TLL1 was set to Unknown
Congenital Heart Defect v0.0 TGFBR2 Zornitza Stark gene: TGFBR2 was added
gene: TGFBR2 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: TGFBR2 was set to Unknown
Congenital Heart Defect v0.0 TGFBR1 Zornitza Stark gene: TGFBR1 was added
gene: TGFBR1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: TGFBR1 was set to Unknown
Congenital Heart Defect v0.0 TFAP2B Zornitza Stark gene: TFAP2B was added
gene: TFAP2B was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: TFAP2B was set to Unknown
Congenital Heart Defect v0.0 TBX5 Zornitza Stark gene: TBX5 was added
gene: TBX5 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: TBX5 was set to Unknown
Congenital Heart Defect v0.0 TBX20 Zornitza Stark gene: TBX20 was added
gene: TBX20 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: TBX20 was set to Unknown
Congenital Heart Defect v0.0 TBX1 Zornitza Stark gene: TBX1 was added
gene: TBX1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: TBX1 was set to Unknown
Congenital Heart Defect v0.0 TAB2 Zornitza Stark gene: TAB2 was added
gene: TAB2 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: TAB2 was set to Unknown
Congenital Heart Defect v0.0 STRA6 Zornitza Stark gene: STRA6 was added
gene: STRA6 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: STRA6 was set to Unknown
Congenital Heart Defect v0.0 SOS1 Zornitza Stark gene: SOS1 was added
gene: SOS1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: SOS1 was set to Unknown
Congenital Heart Defect v0.0 SON Zornitza Stark gene: SON was added
gene: SON was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: SON was set to Unknown
Congenital Heart Defect v0.0 SMC3 Zornitza Stark gene: SMC3 was added
gene: SMC3 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: SMC3 was set to Unknown
Congenital Heart Defect v0.0 SMC1A Zornitza Stark gene: SMC1A was added
gene: SMC1A was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: SMC1A was set to Unknown
Congenital Heart Defect v0.0 SMARCE1 Zornitza Stark gene: SMARCE1 was added
gene: SMARCE1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: SMARCE1 was set to Unknown
Congenital Heart Defect v0.0 SMARCB1 Zornitza Stark gene: SMARCB1 was added
gene: SMARCB1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: SMARCB1 was set to Unknown
Congenital Heart Defect v0.0 SMARCA4 Zornitza Stark gene: SMARCA4 was added
gene: SMARCA4 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: SMARCA4 was set to Unknown
Congenital Heart Defect v0.0 SMAD6 Zornitza Stark gene: SMAD6 was added
gene: SMAD6 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: SMAD6 was set to Unknown
Congenital Heart Defect v0.0 SMAD4 Zornitza Stark gene: SMAD4 was added
gene: SMAD4 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: SMAD4 was set to Unknown
Congenital Heart Defect v0.0 SMAD3 Zornitza Stark gene: SMAD3 was added
gene: SMAD3 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: SMAD3 was set to Unknown
Congenital Heart Defect v0.0 SHOC2 Zornitza Stark gene: SHOC2 was added
gene: SHOC2 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: SHOC2 was set to Unknown
Congenital Heart Defect v0.0 SF3B4 Zornitza Stark gene: SF3B4 was added
gene: SF3B4 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: SF3B4 was set to Unknown
Congenital Heart Defect v0.0 SALL4 Zornitza Stark gene: SALL4 was added
gene: SALL4 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: SALL4 was set to Unknown
Congenital Heart Defect v0.0 SALL1 Zornitza Stark gene: SALL1 was added
gene: SALL1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: SALL1 was set to Unknown
Congenital Heart Defect v0.0 RIT1 Zornitza Stark gene: RIT1 was added
gene: RIT1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: RIT1 was set to Unknown
Congenital Heart Defect v0.0 RAF1 Zornitza Stark gene: RAF1 was added
gene: RAF1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: RAF1 was set to Unknown
Congenital Heart Defect v0.0 RAD21 Zornitza Stark gene: RAD21 was added
gene: RAD21 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: RAD21 was set to Unknown
Congenital Heart Defect v0.0 RAB23 Zornitza Stark gene: RAB23 was added
gene: RAB23 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: RAB23 was set to Unknown
Congenital Heart Defect v0.0 PTPN11 Zornitza Stark gene: PTPN11 was added
gene: PTPN11 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: PTPN11 was set to Unknown
Congenital Heart Defect v0.0 PRKD1 Zornitza Stark gene: PRKD1 was added
gene: PRKD1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: PRKD1 was set to Unknown
Congenital Heart Defect v0.0 PRDM6 Zornitza Stark gene: PRDM6 was added
gene: PRDM6 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: PRDM6 was set to Unknown
Congenital Heart Defect v0.0 PITX2 Zornitza Stark gene: PITX2 was added
gene: PITX2 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: PITX2 was set to Unknown
Congenital Heart Defect v0.0 PBX1 Zornitza Stark gene: PBX1 was added
gene: PBX1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: PBX1 was set to Unknown
Congenital Heart Defect v0.0 NSD1 Zornitza Stark gene: NSD1 was added
gene: NSD1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: NSD1 was set to Unknown
Congenital Heart Defect v0.0 NRAS Zornitza Stark gene: NRAS was added
gene: NRAS was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: NRAS was set to Unknown
Congenital Heart Defect v0.0 NR2F2 Zornitza Stark gene: NR2F2 was added
gene: NR2F2 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: NR2F2 was set to Unknown
Congenital Heart Defect v0.0 NPHP4 Zornitza Stark gene: NPHP4 was added
gene: NPHP4 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: NPHP4 was set to Unknown
Congenital Heart Defect v0.0 NPHP3 Zornitza Stark gene: NPHP3 was added
gene: NPHP3 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: NPHP3 was set to Unknown
Congenital Heart Defect v0.0 NOTCH2 Zornitza Stark gene: NOTCH2 was added
gene: NOTCH2 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: NOTCH2 was set to Unknown
Congenital Heart Defect v0.0 NOTCH1 Zornitza Stark gene: NOTCH1 was added
gene: NOTCH1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: NOTCH1 was set to Unknown
Congenital Heart Defect v0.0 NODAL Zornitza Stark gene: NODAL was added
gene: NODAL was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: NODAL was set to Unknown
Congenital Heart Defect v0.0 NKX2-6 Zornitza Stark gene: NKX2-6 was added
gene: NKX2-6 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: NKX2-6 was set to Unknown
Congenital Heart Defect v0.0 NKX2-5 Zornitza Stark gene: NKX2-5 was added
gene: NKX2-5 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: NKX2-5 was set to Unknown
Congenital Heart Defect v0.0 NIPBL Zornitza Stark gene: NIPBL was added
gene: NIPBL was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: NIPBL was set to Unknown
Congenital Heart Defect v0.0 NF1 Zornitza Stark gene: NF1 was added
gene: NF1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: NF1 was set to Unknown
Congenital Heart Defect v0.0 MYH7 Zornitza Stark gene: MYH7 was added
gene: MYH7 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: MYH7 was set to Unknown
Congenital Heart Defect v0.0 MYH6 Zornitza Stark gene: MYH6 was added
gene: MYH6 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: MYH6 was set to Unknown
Congenital Heart Defect v0.0 MYH11 Zornitza Stark gene: MYH11 was added
gene: MYH11 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: MYH11 was set to Unknown
Congenital Heart Defect v0.0 MYBPC3 Zornitza Stark gene: MYBPC3 was added
gene: MYBPC3 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: MYBPC3 was set to Unknown
Congenital Heart Defect v0.0 MESP1 Zornitza Stark gene: MESP1 was added
gene: MESP1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: MESP1 was set to Unknown
Congenital Heart Defect v0.0 MEIS2 Zornitza Stark gene: MEIS2 was added
gene: MEIS2 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: MEIS2 was set to Unknown
Congenital Heart Defect v0.0 MED13L Zornitza Stark gene: MED13L was added
gene: MED13L was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: MED13L was set to Unknown
Congenital Heart Defect v0.0 MAP2K2 Zornitza Stark gene: MAP2K2 was added
gene: MAP2K2 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: MAP2K2 was set to Unknown
Congenital Heart Defect v0.0 MAP2K1 Zornitza Stark gene: MAP2K1 was added
gene: MAP2K1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: MAP2K1 was set to Unknown
Congenital Heart Defect v0.0 KRAS Zornitza Stark gene: KRAS was added
gene: KRAS was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: KRAS was set to Unknown
Congenital Heart Defect v0.0 KMT2D Zornitza Stark gene: KMT2D was added
gene: KMT2D was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: KMT2D was set to Unknown
Congenital Heart Defect v0.0 KMT2B Zornitza Stark gene: KMT2B was added
gene: KMT2B was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: KMT2B was set to Unknown
Congenital Heart Defect v0.0 KMT2A Zornitza Stark gene: KMT2A was added
gene: KMT2A was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: KMT2A was set to Unknown
Congenital Heart Defect v0.0 KDM6A Zornitza Stark gene: KDM6A was added
gene: KDM6A was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: KDM6A was set to Unknown
Congenital Heart Defect v0.0 KAT6B Zornitza Stark gene: KAT6B was added
gene: KAT6B was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: KAT6B was set to Unknown
Congenital Heart Defect v0.0 KAT6A Zornitza Stark gene: KAT6A was added
gene: KAT6A was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: KAT6A was set to Unknown
Congenital Heart Defect v0.0 KANSL1 Zornitza Stark gene: KANSL1 was added
gene: KANSL1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: KANSL1 was set to Unknown
Congenital Heart Defect v0.0 JAG1 Zornitza Stark gene: JAG1 was added
gene: JAG1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: JAG1 was set to Unknown
Congenital Heart Defect v0.0 INVS Zornitza Stark gene: INVS was added
gene: INVS was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: INVS was set to Unknown
Congenital Heart Defect v0.0 HRAS Zornitza Stark gene: HRAS was added
gene: HRAS was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: HRAS was set to Unknown
Congenital Heart Defect v0.0 HAND2 Zornitza Stark gene: HAND2 was added
gene: HAND2 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: HAND2 was set to Unknown
Congenital Heart Defect v0.0 HAND1 Zornitza Stark gene: HAND1 was added
gene: HAND1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: HAND1 was set to Unknown
Congenital Heart Defect v0.0 GPC3 Zornitza Stark gene: GPC3 was added
gene: GPC3 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: GPC3 was set to Unknown
Congenital Heart Defect v0.0 GJA1 Zornitza Stark gene: GJA1 was added
gene: GJA1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: GJA1 was set to Unknown
Congenital Heart Defect v0.0 GDF1 Zornitza Stark gene: GDF1 was added
gene: GDF1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: GDF1 was set to Unknown
Congenital Heart Defect v0.0 GATA6 Zornitza Stark gene: GATA6 was added
gene: GATA6 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: GATA6 was set to Unknown
Congenital Heart Defect v0.0 GATA5 Zornitza Stark gene: GATA5 was added
gene: GATA5 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: GATA5 was set to Unknown
Congenital Heart Defect v0.0 GATA4 Zornitza Stark gene: GATA4 was added
gene: GATA4 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: GATA4 was set to Unknown
Congenital Heart Defect v0.0 FOXH1 Zornitza Stark gene: FOXH1 was added
gene: FOXH1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: FOXH1 was set to Unknown
Congenital Heart Defect v0.0 FOXC2 Zornitza Stark gene: FOXC2 was added
gene: FOXC2 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: FOXC2 was set to Unknown
Congenital Heart Defect v0.0 FOXC1 Zornitza Stark gene: FOXC1 was added
gene: FOXC1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: FOXC1 was set to Unknown
Congenital Heart Defect v0.0 FLT4 Zornitza Stark gene: FLT4 was added
gene: FLT4 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: FLT4 was set to Unknown
Congenital Heart Defect v0.0 FLNA Zornitza Stark gene: FLNA was added
gene: FLNA was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: FLNA was set to Unknown
Congenital Heart Defect v0.0 FGFR2 Zornitza Stark gene: FGFR2 was added
gene: FGFR2 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: FGFR2 was set to Unknown
Congenital Heart Defect v0.0 FBN1 Zornitza Stark gene: FBN1 was added
gene: FBN1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: FBN1 was set to Unknown
Congenital Heart Defect v0.0 EVC2 Zornitza Stark gene: EVC2 was added
gene: EVC2 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: EVC2 was set to Unknown
Congenital Heart Defect v0.0 EVC Zornitza Stark gene: EVC was added
gene: EVC was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: EVC was set to Unknown
Congenital Heart Defect v0.0 ELN Zornitza Stark gene: ELN was added
gene: ELN was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: ELN was set to Unknown
Congenital Heart Defect v0.0 EHMT1 Zornitza Stark gene: EHMT1 was added
gene: EHMT1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: EHMT1 was set to Unknown
Congenital Heart Defect v0.0 EFTUD2 Zornitza Stark gene: EFTUD2 was added
gene: EFTUD2 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: EFTUD2 was set to Unknown
Congenital Heart Defect v0.0 DOCK6 Zornitza Stark gene: DOCK6 was added
gene: DOCK6 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: DOCK6 was set to Unknown
Congenital Heart Defect v0.0 DLL4 Zornitza Stark gene: DLL4 was added
gene: DLL4 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: DLL4 was set to Unknown
Congenital Heart Defect v0.0 CRELD1 Zornitza Stark gene: CRELD1 was added
gene: CRELD1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: CRELD1 was set to Unknown
Congenital Heart Defect v0.0 CREBBP Zornitza Stark gene: CREBBP was added
gene: CREBBP was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: CREBBP was set to Unknown
Congenital Heart Defect v0.0 CITED2 Zornitza Stark gene: CITED2 was added
gene: CITED2 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: CITED2 was set to Unknown
Congenital Heart Defect v0.0 CHD7 Zornitza Stark gene: CHD7 was added
gene: CHD7 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: CHD7 was set to Unknown
Congenital Heart Defect v0.0 CHD4 Zornitza Stark gene: CHD4 was added
gene: CHD4 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: CHD4 was set to Unknown
Congenital Heart Defect v0.0 CDK13 Zornitza Stark gene: CDK13 was added
gene: CDK13 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: CDK13 was set to Unknown
Congenital Heart Defect v0.0 BRAF Zornitza Stark gene: BRAF was added
gene: BRAF was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: BRAF was set to Unknown
Congenital Heart Defect v0.0 BMPR2 Zornitza Stark gene: BMPR2 was added
gene: BMPR2 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: BMPR2 was set to Unknown
Congenital Heart Defect v0.0 BCOR Zornitza Stark gene: BCOR was added
gene: BCOR was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: BCOR was set to Unknown
Congenital Heart Defect v0.0 B3GAT3 Zornitza Stark gene: B3GAT3 was added
gene: B3GAT3 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: B3GAT3 was set to Unknown
Congenital Heart Defect v0.0 ARID1B Zornitza Stark gene: ARID1B was added
gene: ARID1B was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: ARID1B was set to Unknown
Congenital Heart Defect v0.0 ARID1A Zornitza Stark gene: ARID1A was added
gene: ARID1A was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: ARID1A was set to Unknown
Congenital Heart Defect v0.0 ANKRD11 Zornitza Stark gene: ANKRD11 was added
gene: ANKRD11 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: ANKRD11 was set to Unknown
Congenital Heart Defect v0.0 ADAMTS10 Zornitza Stark gene: ADAMTS10 was added
gene: ADAMTS10 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: ADAMTS10 was set to Unknown
Congenital Heart Defect v0.0 ACVR2B Zornitza Stark gene: ACVR2B was added
gene: ACVR2B was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: ACVR2B was set to Unknown
Congenital Heart Defect v0.0 ACVR1 Zornitza Stark gene: ACVR1 was added
gene: ACVR1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: ACVR1 was set to Unknown
Congenital Heart Defect v0.0 ACTC1 Zornitza Stark gene: ACTC1 was added
gene: ACTC1 was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: ACTC1 was set to Unknown
Congenital Heart Defect v0.0 Zornitza Stark Added panel Congenital Heart Defect_VCGS