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Aortopathy_Connective Tissue Disorders v1.86 SLC2A10 Sangavi Sivagnanasundram reviewed gene: SLC2A10: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008487; Phenotypes: arterial tortuosity syndrome MONDO:0008818; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Aortopathy_Connective Tissue Disorders v1.86 EMILIN1 Zornitza Stark Phenotypes for gene: EMILIN1 were changed from Neuronopathy, distal hereditary motor, type X, MIM# 620080 Aortic aneurysm, MONDO:0005160, EMILIN2-related to Neuronopathy, distal hereditary motor, type X, MIM# 620080; Arterial tortuosity-bone fragility syndrome, MIM# 620908
Aortopathy_Connective Tissue Disorders v1.85 EMILIN1 Zornitza Stark edited their review of gene: EMILIN1: Changed phenotypes: Neuronopathy, distal hereditary motor, type X, MIM# 620080, Peripheral neuropathy
Aortopathy_Connective Tissue Disorders v1.85 EMILIN1 Zornitza Stark edited their review of gene: EMILIN1: Changed phenotypes: Neuronopathy, distal hereditary motor, type X, MIM# 620080, Peripheral neuropathy, Arterial tortuosity-bone fragility syndrome, MIM# 620908
Aortopathy_Connective Tissue Disorders v1.85 THBS2 Zornitza Stark Phenotypes for gene: THBS2 were changed from connective tissue disorder MONDO:0003900, THBS2-related to Ehlers-Danlos syndrome, classic type, 3, MIM# 620865
Aortopathy_Connective Tissue Disorders v1.84 THBS2 Zornitza Stark reviewed gene: THBS2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Ehlers-Danlos syndrome, classic type, 3, MIM# 620865; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v1.84 EMILIN1 Chern Lim reviewed gene: EMILIN1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuronopathy, distal hereditary motor, autosomal dominant 10, MIM#620080, Aortic aneurysm, MONDO:0005160, EMILIN1-related, AR.; Mode of inheritance: None
Aortopathy_Connective Tissue Disorders v1.84 EFEMP1 Zornitza Stark Phenotypes for gene: EFEMP1 were changed from EFEMP1-related connective tissue disorder; cutis laxa to Cutis laxa, autosomal recessive, type ID, MIM# 620780
Aortopathy_Connective Tissue Disorders v1.83 EFEMP1 Zornitza Stark edited their review of gene: EFEMP1: Changed phenotypes: Cutis laxa, autosomal recessive, type ID, MIM# 620780
Aortopathy_Connective Tissue Disorders v1.83 THBS2 Chris Ciotta Deleted their comment
Aortopathy_Connective Tissue Disorders v1.83 THBS2 Chris Ciotta Deleted their comment
Aortopathy_Connective Tissue Disorders v1.83 THBS2 Chris Ciotta Deleted their comment
Aortopathy_Connective Tissue Disorders v1.83 THBS2 Chris Ciotta Deleted their comment
Aortopathy_Connective Tissue Disorders v1.83 THBS2 Ain Roesley Phenotypes for gene: THBS2 were changed from connective tissue disorder MONDO:0003900, THBS2-related to connective tissue disorder MONDO:0003900, THBS2-related
Aortopathy_Connective Tissue Disorders v1.83 THBS2 Ain Roesley Marked gene: THBS2 as ready
Aortopathy_Connective Tissue Disorders v1.83 THBS2 Ain Roesley Gene: thbs2 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v1.83 THBS2 Ain Roesley Phenotypes for gene: THBS2 were changed from connective tissue disorder MONDO:0003900, THBS2-related to connective tissue disorder MONDO:0003900, THBS2-related
Aortopathy_Connective Tissue Disorders v1.82 THBS2 Ain Roesley Phenotypes for gene: THBS2 were changed from Ehlers-Danlos syndrome to connective tissue disorder MONDO:0003900, THBS2-related
Aortopathy_Connective Tissue Disorders v1.82 THBS2 Chris Ciotta edited their review of gene: THBS2: Added comment: One family with autosomal dominant inheritance of a THBS2 missense variant (NM_003247.5:c.2686T>C p.Cys896Arg). The index patient in this family presented with a history of multiple joint dislocations, easy bruising, prolonged wound healing and a diagnosis of bilateral greater saphenous vein insufficiency.

This individual's mother who also carries the variant was noted as having prolonged bleeding, thickened mitral valve and dilated aortic arch.

No other variants in 15 known EDS-related genes were identified in the index individual. Sanger sequencing confirmed this variants presence in the two other affected family members and its absence in an unaffected member.

Mouse knock-in of this variant demonstrated that mutant mice had hyper-flexibility of their tails and dramatically longer bleeding times when compared with wildtype mice.; Changed phenotypes: connective tissue disorder MONDO:0003900, THBS2-related
Aortopathy_Connective Tissue Disorders v1.82 THBS2 Ain Roesley Classified gene: THBS2 as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v1.82 THBS2 Ain Roesley Gene: thbs2 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v1.82 THBS2 Ain Roesley Classified gene: THBS2 as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v1.82 THBS2 Ain Roesley Gene: thbs2 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v1.81 THBS2 Chris Ciotta commented on gene: THBS2: One family with autosomal dominant inheritance of a THBS2 missense variant (NM_003247.5:c.2686T>C p.Cys896Arg). The index patient in this family presented with a history of multiple joint dislocations, easy bruising, prolonged wound healing and a diagnosis of bilateral greater saphenous vein insufficiency.

This individual's mother who also carries the variant was noted as having prolonged bleeding, thickened mitral valve and dilated aortic arch.

No other variants in 15 known EDS-related genes were identified in the index individual. Sanger sequencing confirmed this variants presence in the two other affected family members and its absence in an unaffected member.

Mouse knock-in of this variant demonstrated that mutant mice had hyper-flexibility of their tails and dramatically longer bleeding times when compared with wildtype mice.
Aortopathy_Connective Tissue Disorders v1.81 THBS2 Chris Ciotta commented on gene: THBS2: One family with autosomal dominant inheritance of a THBS2 missense variant (NM_003247.5:c.2686T>C p.Cys896Arg). The index patient in this family presented with a history of multiple joint dislocations, easy bruising, prolonged wound healing and a diagnosis of bilateral greater saphenous vein insufficiency.

This individual's mother who also carries the variant was noted as having prolonged bleeding, thickened mitral valve and dilated aortic arch.

No other variants in 15 known EDS-related genes were identified in the index individual. Sanger sequencing confirmed this variants presence in the two other affected family members and its absence in an unaffected member.

Mouse knock-in of this variant demonstrated that mutant mice had hyper-flexibility of their tails and dramatically longer bleeding times when compared with wildtype mice.
Aortopathy_Connective Tissue Disorders v1.81 THBS2 Chris Ciotta edited their review of gene: THBS2: Added comment: One family with autosomal dominant inheritance of a THBS2 missense variant (NM_003247.5:c.2686T>C p.Cys896Arg). The index patient in this family presented with a history of multiple joint dislocations, easy bruising, prolonged wound healing and a diagnosis of bilateral greater saphenous vein insufficiency.

This individual's mother who also carries the variant was noted as having prolonged bleeding, thickened mitral valve and dilated aortic arch.

No other variants in 15 known EDS-related genes were identified in the index individual. Sanger sequencing confirmed this variants presence in the two other affected family members and its absence in an unaffected member.

Mouse knock-in of this variant demonstrated that mutant mice had hyper-flexibility of their tails and dramatically longer bleeding times when compared with wildtype mice.; Changed phenotypes: connective tissue disorder MONDO:0003900
Aortopathy_Connective Tissue Disorders v1.81 THBS2 Ain Roesley Classified gene: THBS2 as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v1.81 THBS2 Ain Roesley Gene: thbs2 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v1.81 THBS2 Ain Roesley Classified gene: THBS2 as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v1.81 THBS2 Ain Roesley Gene: thbs2 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v1.80 THBS2 Chris Ciotta changed review comment from: One family with autosomal dominant inheritance of a THBS2 missense variant (NM_003247.5:c.2686T>C p.Cys896Arg). The index patient in this family presented with a history of multiple joint dislocations, easy bruising, prolonged wound healing and a diagnosis of bilateral greater saphenous vein insufficiency.

This individual's mother who also carries the variant was noted as having prolonged bleeding, thickened mitral valve and dilated aortic arch.

No other variants in 15 known EDS-related genes was identified in the index individual. Sanger sequencing confirmed this variants presence in the two other affected family members and its absence in an unaffected member.

Mouse knock-in of this variant demonstrated that mutant mice had hyper-flexibility of their tails and dramatically longer bleeding times when compared with wildtype mice.
Sources: Literature; to: One family with autosomal dominant inheritance of a THBS2 missense variant (NM_003247.5:c.2686T>C p.Cys896Arg). The index patient in this family presented with a history of multiple joint dislocations, easy bruising, prolonged wound healing and a diagnosis of bilateral greater saphenous vein insufficiency.

This individual's mother who also carries the variant was noted as having prolonged bleeding, thickened mitral valve and dilated aortic arch.

No other variants in 15 known EDS-related genes were identified in the index individual. Sanger sequencing confirmed this variants presence in the two other affected family members and its absence in an unaffected member.

Mouse knock-in of this variant demonstrated that mutant mice had hyper-flexibility of their tails and dramatically longer bleeding times when compared with wildtype mice.
Sources: Literature
Aortopathy_Connective Tissue Disorders v1.80 THBS2 Chris Ciotta gene: THBS2 was added
gene: THBS2 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: THBS2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: THBS2 were set to PMID: 38433265
Phenotypes for gene: THBS2 were set to Ehlers-Danlos syndrome
Penetrance for gene: THBS2 were set to Complete
Review for gene: THBS2 was set to AMBER
Added comment: One family with autosomal dominant inheritance of a THBS2 missense variant (NM_003247.5:c.2686T>C p.Cys896Arg). The index patient in this family presented with a history of multiple joint dislocations, easy bruising, prolonged wound healing and a diagnosis of bilateral greater saphenous vein insufficiency.

This individual's mother who also carries the variant was noted as having prolonged bleeding, thickened mitral valve and dilated aortic arch.

No other variants in 15 known EDS-related genes was identified in the index individual. Sanger sequencing confirmed this variants presence in the two other affected family members and its absence in an unaffected member.

Mouse knock-in of this variant demonstrated that mutant mice had hyper-flexibility of their tails and dramatically longer bleeding times when compared with wildtype mice.
Sources: Literature
Aortopathy_Connective Tissue Disorders v1.80 COL12A1 Elena Savva Publications for gene: COL12A1 were set to 28306229; 31273343; 24334604
Aortopathy_Connective Tissue Disorders v1.79 COL12A1 Elena Savva reviewed gene: COL12A1: Rating: ; Mode of pathogenicity: None; Publications: 37458870, 37353357; Phenotypes: ; Mode of inheritance: None
Aortopathy_Connective Tissue Disorders v1.79 ARIH1 Zornitza Stark Phenotypes for gene: ARIH1 were changed from Thoracic aortic aneurysm to Thoracic aortic aneurysm, MONDO:0005396, ARIH1-related
Aortopathy_Connective Tissue Disorders v1.78 PMEPA1 Zornitza Stark Marked gene: PMEPA1 as ready
Aortopathy_Connective Tissue Disorders v1.78 PMEPA1 Zornitza Stark Gene: pmepa1 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v1.78 PMEPA1 Zornitza Stark Classified gene: PMEPA1 as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v1.78 PMEPA1 Zornitza Stark Gene: pmepa1 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v1.77 PMEPA1 Zornitza Stark gene: PMEPA1 was added
gene: PMEPA1 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: PMEPA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PMEPA1 were set to 36928819
Phenotypes for gene: PMEPA1 were set to Hereditary disorder of connective tissue, MONDO:0023603, PMEPA1-related
Mode of pathogenicity for gene: PMEPA1 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: PMEPA1 was set to AMBER
Added comment: PMID: 36928819; Greene, D. et al. (2023) Nat Med. 29(3):679-688.
A paper by Genomics England Research Consortium. Genetic association analysis of 77,539 genomes .

Eight families with truncating variants affecting the same stretch of cytosines in this gene.

In the 100KGP discovery cohort, in three families with Familial thoracic aortic aneurysm disease (FTAAD) of European ancestry, the variant found was an insertion of a cytosine within a seven-cytosine stretch in the last exon, predicted to cause p.(S209Qfs*3). This variant was also identified independently in eight affected members of three pedigrees of Japanese ancestry in a separate Japanese patient group.
(Note: the variant is present in gnomAD v2.1.1 in 22 heterozygotes as a filtered out variant.).

Also, this study found a deletion of one of those cytosines causing p.(S209Afs*61), in one individual or family.
Also, there was one family in Belgium in which the affected members carried a 5-bp deletion in the same stretch of polycytosines inducing a frameshift p.(P207Qfs*3).

Phenotypic analysis of the individuals suggest that the phenotype of these FTAAD individuals and families is more like Loeys-Dietz syndrome.
Sources: Literature
Aortopathy_Connective Tissue Disorders v1.76 TGFBR1 Alison Yeung Mode of inheritance for gene: TGFBR1 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Aortopathy_Connective Tissue Disorders v1.76 TGFBR1 Alison Yeung Mode of inheritance for gene: TGFBR1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Aortopathy_Connective Tissue Disorders v1.75 TGFBR1 Alison Yeung reviewed gene: TGFBR1: Rating: ; Mode of pathogenicity: None; Publications: 36584339; Phenotypes: Loeys-Dietz syndrome 1, MIM# 609192; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Aortopathy_Connective Tissue Disorders v1.75 EMILIN1 Zornitza Stark Marked gene: EMILIN1 as ready
Aortopathy_Connective Tissue Disorders v1.75 EMILIN1 Zornitza Stark Gene: emilin1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.75 EMILIN1 Zornitza Stark Publications for gene: EMILIN1 were set to PMID: 36351433
Aortopathy_Connective Tissue Disorders v1.74 EMILIN1 Zornitza Stark reviewed gene: EMILIN1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31978608, 26462740; Phenotypes: Neuronopathy, distal hereditary motor, type X, MIM# 620080, Peripheral neuropathy, aortic aneurysm; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v1.74 EMILIN1 Zornitza Stark Classified gene: EMILIN1 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.74 EMILIN1 Zornitza Stark Gene: emilin1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.73 EMILIN1 Karina Sandoval gene: EMILIN1 was added
gene: EMILIN1 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: EMILIN1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: EMILIN1 were set to PMID: 36351433
Phenotypes for gene: EMILIN1 were set to Neuronopathy, distal hereditary motor, type X, MIM# 620080 Aortic aneurysm, MONDO:0005160, EMILIN2-related
Review for gene: EMILIN1 was set to GREEN
Added comment: Bi-allelic EMILIN1 loss-of-function variants causative for an entity combining cutis laxa, arterial tortuosity, aneurysm formation, and bone fragility, and transient osteopenia

4 families - Variants segregated in the all families, carriers
Fam 1. 2 affected, homozygous c.831dup consanguineous
Fam 2. 2 affected homozygous c.151del consanguineous
Fam 3. 1 affected chet
Fam 4. 1 affected homozygous c.1606C>T

Mouse models
All affected individuals presented with generalized arterial tortuosity and fractures
Sources: Literature
Aortopathy_Connective Tissue Disorders v1.73 LTBP3 Zornitza Stark Classified gene: LTBP3 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.73 LTBP3 Zornitza Stark Gene: ltbp3 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.72 LTBP3 Krithika Murali changed review comment from: 3rd individual reported with dissection of the descending aorta in adulthood. WES identified compound heterozygous LTBP3 frameshift variants predicted to undergo NMD (confirmed in trans through familial segregation studies), this individual also had spinal stenosis and dental anomalies. His offspring with heterozygous variants had no aortic or other anomalies.

Association between heterozygous variants (both missense and NMD-predicted) and later-onset thoracic aortic dissection postulated - AMBER association.; to: 3rd individual reported with dissection of the descending aorta in adulthood. WES identified compound heterozygous LTBP3 frameshift variants predicted to undergo NMD (confirmed in trans through familial segregation studies), this individual also had spinal stenosis and dental anomalies. His offspring with heterozygous variants had no aortic or other anomalies.

Association between heterozygous variants (both missense and NMD-predicted) and later-onset thoracic aortic dissection postulated - AMBER association.
Aortopathy_Connective Tissue Disorders v1.72 LTBP3 Krithika Murali reviewed gene: LTBP3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34906192; Phenotypes: Dental anomalies and short stature - MIM#601216, thoracic aortic aneurysms; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Aortopathy_Connective Tissue Disorders v1.72 CBS Zornitza Stark Tag treatable tag was added to gene: CBS.
Aortopathy_Connective Tissue Disorders v1.72 ATP7A Zornitza Stark Tag treatable tag was added to gene: ATP7A.
Aortopathy_Connective Tissue Disorders v1.72 ATP7A Zornitza Stark changed review comment from: Connective tissue laxity is a prominent part of the phenotype.
Sources: Expert list; to: Connective tissue laxity is a prominent part of the phenotype.

Treatment: subcutaneous injections of copper histidine or copper chloride

ClinGen has assessed as moderate evidence for actionability.

Neonatal treatment with subcutaneous copper-histidine (initiated before 30 days of life) is recommended for asymptomatic males with a diagnosis of MD, but is not recommended for symptomatic boys or after 30 days of life. Treatment should be continued indefinitely. In an open-label clinical trial, 12 patients with MD treated with copper-histidine within 22 days of life had 92% survival after a mean follow-up of 4.6 years compared to 13% in a historical control group of 15 patients treated after a late diagnosis (mean age at diagnosis: 163 ± 113 days, range: 42 to 390). Two of the 12 patients with earlier treatment had normal neurological development. A second open-label trial of 35 presymptomatic patients receiving copper-histidine at less than a month of age reported significant improvement of four major neurodevelopmental (gross motor, fine motor/adaptive, personal/social, and language) domains and a non-significant lower mortality (28.5% vs 50%) at age of 3 years (or age of death) compared to 22 patients treated later and after onset of symptoms.
Sources: Expert list
Aortopathy_Connective Tissue Disorders v1.72 Zornitza Stark List of related panels changed from to Aortic aneurysm; HP:0004942;Joint dislocation; HP:0001373;Cutis laxa; HP:0000973; Ectopia lentis; HP:0001083;Arachnodactyly; HP:0001166
Aortopathy_Connective Tissue Disorders v1.71 JAG1 Bryony Thompson Marked gene: JAG1 as ready
Aortopathy_Connective Tissue Disorders v1.71 JAG1 Bryony Thompson Gene: jag1 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v1.71 JAG1 Bryony Thompson Classified gene: JAG1 as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v1.71 JAG1 Bryony Thompson Gene: jag1 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v1.70 JAG1 Bryony Thompson gene: JAG1 was added
gene: JAG1 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: JAG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JAG1 were set to 35819173; 30071989; 14993126; 18570795
Phenotypes for gene: JAG1 were set to thoracic aortic aneurysm MONDO:0005396
Review for gene: JAG1 was set to AMBER
Added comment: Thoracic aortic aneurysm appears to be a rare feature of Alagille syndrome, but has been reported as a presenting feature in at least 2 families
PMID: 35819173 - two families segregating JAG1 variants that present with isolated aneurysmal disease lacking other Alagille syndrome (AGS) clinical characteristics (such as the hepatic abnormalities, posterior embryotoxon, and cardiac structural changes). Histological evaluation of aortic tissue from one of the TAA cases revealed elastin degradation and abnormal collagen deposition.
PMID: 30071989 - JAG1 assessed as no (clinical) evidence for HTAAD by the ClinGen Heritable Thoracic Aortic Aneurysm and Dissection GCEP in 2018. Currently under review
PMID: 14993126 - three AGS patients with aortic aneurysms and 2 with aortic coarctations identified in a retrospective chart review of 268 AGS individuals autopsy finding in three patients who died of sudden death
PMID: 18570795 - 17 yo asymptomatic AGS case with dilatation of the ascending aorta from the root identified
Sources: Literature
Aortopathy_Connective Tissue Disorders v1.69 Zornitza Stark HPO terms changed from to Aortic aneurysm, HP:0004942;Joint dislocation, HP:0001373;Cutis laxa, HP:0000973; Ectopia lentis, HP:0001083;Arachnodactyly, HP:0001166
Aortopathy_Connective Tissue Disorders v1.68 ROBO4 Zornitza Stark Classified gene: ROBO4 as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v1.68 ROBO4 Zornitza Stark Gene: robo4 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v1.67 ROBO4 Zornitza Stark Deleted their comment
Aortopathy_Connective Tissue Disorders v1.67 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
Aortopathy_Connective Tissue Disorders v1.67 COL11A1 Zornitza Stark Marked gene: COL11A1 as ready
Aortopathy_Connective Tissue Disorders v1.67 COL11A1 Zornitza Stark Gene: col11a1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.67 THSD4 Zornitza Stark Marked gene: THSD4 as ready
Aortopathy_Connective Tissue Disorders v1.67 THSD4 Zornitza Stark Gene: thsd4 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.67 THSD4 Zornitza Stark Phenotypes for gene: THSD4 were changed from Thoracic aortic aneurysm and dissection (TAAD) to Aortic aneurysm, familial thoracic 12, MIM# 619825
Aortopathy_Connective Tissue Disorders v1.66 THSD4 Zornitza Stark reviewed gene: THSD4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Aortic aneurysm, familial thoracic 12, MIM# 619825; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v1.66 C1S Ain Roesley Publications for gene: C1S were set to 30071989; 27745832; 31921203; 28306229
Aortopathy_Connective Tissue Disorders v1.66 C1S Ain Roesley edited their review of gene: C1S: Changed rating: GREEN; Changed publications: 30071989, 27745832, 31921203, 28306229; Changed phenotypes: Ehlers-Danlos syndrome, periodontal type, 2 MIM#617174; Set current diagnostic: yes
Aortopathy_Connective Tissue Disorders v1.66 C1S Ain Roesley Phenotypes for gene: C1S were changed from Ehlers-Danlos syndrome, periodontal type, 1 (MIM# 130080) to Ehlers-Danlos syndrome, periodontal type, 2 MIM#617174
Aortopathy_Connective Tissue Disorders v1.65 C1S Ain Roesley Classified gene: C1S as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.65 C1S Ain Roesley Gene: c1s has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.64 KCNMA1 Zornitza Stark Marked gene: KCNMA1 as ready
Aortopathy_Connective Tissue Disorders v1.64 KCNMA1 Zornitza Stark Gene: kcnma1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.64 KCNMA1 Zornitza Stark Classified gene: KCNMA1 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.64 KCNMA1 Zornitza Stark Gene: kcnma1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.63 KCNMA1 Zornitza Stark gene: KCNMA1 was added
gene: KCNMA1 was added to Aortopathy_Connective Tissue Disorders. Sources: Expert list
Mode of inheritance for gene: KCNMA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNMA1 were set to 31152168
Phenotypes for gene: KCNMA1 were set to Liang-Wang syndrome, MIM# 618729
Review for gene: KCNMA1 was set to GREEN
Added comment: Mono-allelic and bi-allelic variants in this gene are associated with a range of neurological phenotypes.

However, 8 unrelated individuals reported with de novo missense variants and a multiple malformations syndrome, which includes vascular tortuosity/ectasia and aortic aneurysm as features.
Sources: Expert list
Aortopathy_Connective Tissue Disorders v1.62 TLN1 Bryony Thompson Marked gene: TLN1 as ready
Aortopathy_Connective Tissue Disorders v1.62 TLN1 Bryony Thompson Gene: tln1 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v1.62 TLN1 Bryony Thompson Classified gene: TLN1 as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v1.62 TLN1 Bryony Thompson Gene: tln1 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v1.61 TLN1 Bryony Thompson gene: TLN1 was added
gene: TLN1 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: TLN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TLN1 were set to 30888838
Phenotypes for gene: TLN1 were set to idiopathic spontaneous coronary artery dissection MONDO:0007385
Review for gene: TLN1 was set to AMBER
Added comment: 10 unique rare heterozygous missense variants in 11 individuals were identified in a 2 generation SCAD family and 56 unrelated individuals with sporadic SCAD. All variants had a MAF of less than 0.06% and occurred within highly conserved β-integrin, F-actin, or vinculin binding domains. Incomplete penetrance was evident in the familial case and five individuals with sporadic SCAD from whom parental DNA was available. No functional assays were conducted.
Sources: Literature
Aortopathy_Connective Tissue Disorders v1.60 SMAD2 Zornitza Stark Phenotypes for gene: SMAD2 were changed from Aortic and arterial aneurysmal disease; connective tissue disease to Loeys-Dietz syndrome 6, MIM# 619656
Aortopathy_Connective Tissue Disorders v1.59 SMAD2 Zornitza Stark edited their review of gene: SMAD2: Changed phenotypes: Loeys-Dietz syndrome 6, MIM# 619656
Aortopathy_Connective Tissue Disorders v1.59 DLG4 Zornitza Stark Phenotypes for gene: DLG4 were changed from Intellectual developmental disorder 62, MIM#618793 to Intellectual developmental disorder 62, MIM#618793; Marfanoid features
Aortopathy_Connective Tissue Disorders v1.58 DLG4 Zornitza Stark edited their review of gene: DLG4: Changed phenotypes: Intellectual developmental disorder 62, MIM#618793, Marfanoid features
Aortopathy_Connective Tissue Disorders v1.58 DLG4 Zornitza Stark Marked gene: DLG4 as ready
Aortopathy_Connective Tissue Disorders v1.58 DLG4 Zornitza Stark Gene: dlg4 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.58 DLG4 Zornitza Stark Mode of inheritance for gene: DLG4 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v1.57 DLG4 Zornitza Stark Publications for gene: DLG4 were set to PMID: 33597769
Aortopathy_Connective Tissue Disorders v1.56 DLG4 Zornitza Stark Classified gene: DLG4 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.56 DLG4 Zornitza Stark Gene: dlg4 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.55 DLG4 Zornitza Stark changed review comment from: Marfanoid habits described in multiple affected individuals.; to: Marfanoid habitus described in multiple affected individuals.
Aortopathy_Connective Tissue Disorders v1.55 DLG4 Zornitza Stark reviewed gene: DLG4: Rating: GREEN; Mode of pathogenicity: None; Publications: 29460436; Phenotypes: Intellectual developmental disorder 62, MIM#618793; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v1.55 DLG4 Elena Savva gene: DLG4 was added
gene: DLG4 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: DLG4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DLG4 were set to PMID: 33597769
Phenotypes for gene: DLG4 were set to Intellectual developmental disorder 62, MIM#618793
Review for gene: DLG4 was set to GREEN
Added comment: PMID: 33597769 - joint laxity reported in 13/38 patients, most patient variants were de novo PTCs
Sources: Literature
Aortopathy_Connective Tissue Disorders v1.55 NPR3 Zornitza Stark Phenotypes for gene: NPR3 were changed from Tall stature, skeletal abnormalities, aortic dilatation to Boudin-Mortier syndrome, MIM#619543; Tall stature, skeletal abnormalities, aortic dilatation
Aortopathy_Connective Tissue Disorders v1.54 NPR3 Zornitza Stark edited their review of gene: NPR3: Changed phenotypes: Boudin-Mortier syndrome, MIM#619543, Tall stature, skeletal abnormalities, aortic dilatation
Aortopathy_Connective Tissue Disorders v1.54 LTBP3 Zornitza Stark Marked gene: LTBP3 as ready
Aortopathy_Connective Tissue Disorders v1.54 LTBP3 Zornitza Stark Gene: ltbp3 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v1.54 COL11A1 Bryony Thompson Classified gene: COL11A1 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.54 COL11A1 Bryony Thompson Gene: col11a1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.53 COL11A1 Bryony Thompson gene: COL11A1 was added
gene: COL11A1 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: COL11A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: COL11A1 were set to 8872475; 20301479
Phenotypes for gene: COL11A1 were set to Stickler syndrome, type II MIM#604841
Review for gene: COL11A1 was set to GREEN
gene: COL11A1 was marked as current diagnostic
Added comment: Stickler syndrome is a multi-system connective tissue disorder. Monoallelic loss of function variants in COL11A1 are a well-established cause of Stickler syndrome.
Sources: Literature
Aortopathy_Connective Tissue Disorders v1.52 COL2A1 Bryony Thompson Marked gene: COL2A1 as ready
Aortopathy_Connective Tissue Disorders v1.52 COL2A1 Bryony Thompson Gene: col2a1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.52 COL2A1 Bryony Thompson Classified gene: COL2A1 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.52 COL2A1 Bryony Thompson Gene: col2a1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.51 COL2A1 Bryony Thompson gene: COL2A1 was added
gene: COL2A1 was added to Aortopathy_Connective Tissue Disorders. Sources: Other
Mode of inheritance for gene: COL2A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: COL2A1 were set to 1677770; 20301479
Phenotypes for gene: COL2A1 were set to Stickler syndrome, type I MIM#108300
Review for gene: COL2A1 was set to GREEN
gene: COL2A1 was marked as current diagnostic
Added comment: Stickler syndrome is a multi-system connective tissue disorder. Monoallelic loss of function variants in COL2A1 are the most common cause of Stickler syndrome.
Sources: Other
Aortopathy_Connective Tissue Disorders v1.50 LTBP3 Bryony Thompson Classified gene: LTBP3 as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v1.50 LTBP3 Bryony Thompson Gene: ltbp3 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v1.49 LTBP3 Bryony Thompson gene: LTBP3 was added
gene: LTBP3 was added to Aortopathy_Connective Tissue Disorders. Sources: Other
Mode of inheritance for gene: LTBP3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: LTBP3 were set to 29625025; 34150014
Phenotypes for gene: LTBP3 were set to Thoracic aortic aneurysms and dissections
Review for gene: LTBP3 was set to AMBER
Added comment: 2 families with biallelic variants with thoracic aortic aneurysms and dissections and other arterial aneurysms, along with skeletal and dental defects. TAA hasn't been reported in other dental anomalies and short stature cases with biallelic LTBP3 variants. Individuals with heterozygous mutations in LTBP3 may also be at increased risk for later-onset thoracic aortic disease, 9/338 isolated TAD individuals had rare heterozygous variants. Null mouse model had thoracic aortic aneurysms
Sources: Other
Aortopathy_Connective Tissue Disorders v1.48 ARIH1 Bryony Thompson Marked gene: ARIH1 as ready
Aortopathy_Connective Tissue Disorders v1.48 ARIH1 Bryony Thompson Gene: arih1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.48 ARIH1 Bryony Thompson Classified gene: ARIH1 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.48 ARIH1 Bryony Thompson Gene: arih1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.47 ARIH1 Bryony Thompson gene: ARIH1 was added
gene: ARIH1 was added to Aortopathy_Connective Tissue Disorders. Sources: Other
Mode of inheritance for gene: ARIH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARIH1 were set to 29689197; 32102558
Phenotypes for gene: ARIH1 were set to Thoracic aortic aneurysm
Review for gene: ARIH1 was set to GREEN
Added comment: 3 unrelated families: A de novo case (R171*) with thoracic aortic aneurysm (TAA), and 2 siblings with TAA and a missense (E15Q). Another proband with cerebrovascular aneurysm (family history of TAA) and a missense variant (E44G). Supporting functional assays of the variants and a drosophila model.
Sources: Other
Aortopathy_Connective Tissue Disorders v1.46 ADAMTS17 Bryony Thompson Marked gene: ADAMTS17 as ready
Aortopathy_Connective Tissue Disorders v1.46 ADAMTS17 Bryony Thompson Gene: adamts17 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.46 ADAMTS17 Bryony Thompson Classified gene: ADAMTS17 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.46 ADAMTS17 Bryony Thompson Gene: adamts17 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.45 ADAMTS17 Bryony Thompson gene: ADAMTS17 was added
gene: ADAMTS17 was added to Aortopathy_Connective Tissue Disorders. Sources: Other
Mode of inheritance for gene: ADAMTS17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAMTS17 were set to 19836009; 20301293
Phenotypes for gene: ADAMTS17 were set to Weill-Marchesani 4 syndrome, recessive MIM#613195
Review for gene: ADAMTS17 was set to GREEN
gene: ADAMTS17 was marked as current diagnostic
Added comment: Weill-Marchesani syndrome is a multi-system connective tissue disorder. Biallelic variants in ADAMTS17 have been reported in at least 6 families.
Sources: Other
Aortopathy_Connective Tissue Disorders v1.44 ADAMTS10 Bryony Thompson Marked gene: ADAMTS10 as ready
Aortopathy_Connective Tissue Disorders v1.44 ADAMTS10 Bryony Thompson Gene: adamts10 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.44 ADAMTS10 Bryony Thompson Classified gene: ADAMTS10 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.44 ADAMTS10 Bryony Thompson Gene: adamts10 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.43 ADAMTS10 Bryony Thompson gene: ADAMTS10 was added
gene: ADAMTS10 was added to Aortopathy_Connective Tissue Disorders. Sources: Other
Mode of inheritance for gene: ADAMTS10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAMTS10 were set to 15368195; 20301293
Phenotypes for gene: ADAMTS10 were set to Weill-Marchesani syndrome 1, recessive MIM#277600
Review for gene: ADAMTS10 was set to GREEN
gene: ADAMTS10 was marked as current diagnostic
Added comment: Weill-Marchesani syndrome is a multi-system connective tissue disorder. Biallelic variants in ADAMTS10 have been reported in >10 families.
Sources: Other
Aortopathy_Connective Tissue Disorders v1.42 IPO8 Zornitza Stark Phenotypes for gene: IPO8 were changed from Loeys-Dietz syndrome-like; cardiovascular, neurologic, skeletal and immunologic abnormalities to Vascular aneurysm, immune dysregulation, skeletal anomalies, and skin and joint laxity, MIM# 619472; Loeys-Dietz syndrome-like; cardiovascular, neurologic, skeletal and immunologic abnormalities
Aortopathy_Connective Tissue Disorders v1.41 IPO8 Zornitza Stark edited their review of gene: IPO8: Changed phenotypes: Vascular aneurysm, immune dysregulation, skeletal anomalies, and skin and joint laxity, MIM# 619472
Aortopathy_Connective Tissue Disorders v1.41 LTBP1 Zornitza Stark Phenotypes for gene: LTBP1 were changed from cutis laxa syndrome to Cutis laxa, autosomal recessive, type IIE MIM#619451
Aortopathy_Connective Tissue Disorders v1.40 LTBP1 Zornitza Stark edited their review of gene: LTBP1: Changed phenotypes: cutis laxa, autosomal recessive, type IIE MIM#619451
Aortopathy_Connective Tissue Disorders v1.40 PDGFRB Zornitza Stark Marked gene: PDGFRB as ready
Aortopathy_Connective Tissue Disorders v1.40 PDGFRB Zornitza Stark Gene: pdgfrb has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.40 PDGFRB Zornitza Stark Classified gene: PDGFRB as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.40 PDGFRB Zornitza Stark Gene: pdgfrb has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.39 PDGFRB Zornitza Stark Tag somatic tag was added to gene: PDGFRB.
Aortopathy_Connective Tissue Disorders v1.39 PDGFRB Natasha Brown gene: PDGFRB was added
gene: PDGFRB was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: PDGFRB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PDGFRB were set to PMID: 33683022; 32291752
Phenotypes for gene: PDGFRB were set to aneurysm; scoliosis; atrophic skin; stroke; infantile myofibromatosis
Mode of pathogenicity for gene: PDGFRB 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: PDGFRB was set to GREEN
Added comment: PMID: 33683022 describes 2 new cases of somatic mosaic variants in this gene with connective tissue/Marfanoid/progeriod phenotypes plus overgrowth (multiple aneurysms, varicosities, increased skin elasticity, pulmonary cysts), the same missense variant present in both patients in tissue (PDGFRB (NM_002609.3) c.1685A > G, p.(Tyr562Cys)).
PMID: 32291752 Three unrelated cases with heterozygous activating germline variants reviewed with similar phenotypes to above including early onset stroke/aneurysm.
Sources: Literature
Aortopathy_Connective Tissue Disorders v1.38 LTBP1 Zornitza Stark Marked gene: LTBP1 as ready
Aortopathy_Connective Tissue Disorders v1.38 LTBP1 Zornitza Stark Gene: ltbp1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.38 LTBP1 Zornitza Stark Classified gene: LTBP1 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.38 LTBP1 Zornitza Stark Gene: ltbp1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.37 LTBP1 Zornitza Stark gene: LTBP1 was added
gene: LTBP1 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: LTBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LTBP1 were set to 33991472
Phenotypes for gene: LTBP1 were set to cutis laxa syndrome
Review for gene: LTBP1 was set to GREEN
Added comment: PMID:33991472
- Premature truncating variants in multiple affected individuals from 4 unrelated consanguineous families.
- Affected individuals present with connective tissue features (cutis laxa and inguinal hernia), craniofacial dysmorphology, variable heart defects, and prominent skeletal features (craniosynostosis, short stature, brachydactyly, and syndactyly).
- Functional studies done on patient fibroblasts and zebrafish models.
Sources: Literature
Aortopathy_Connective Tissue Disorders v1.36 ADAMTSL2 Zornitza Stark changed review comment from: Six families reported with same variant. However, in five, no further segregation studies were performed and overall it is unclear whether this is a founder variant or a recurrent variant. No functional data.; to: Six families reported with same variant. However, in five, no further segregation studies were performed and overall it is unclear whether this is a founder variant or a recurrent variant. No functional data.

Note association between bi-allelic variants and geleophysic dysplasia is well established.
Aortopathy_Connective Tissue Disorders v1.36 ADAMTSL2 Zornitza Stark Marked gene: ADAMTSL2 as ready
Aortopathy_Connective Tissue Disorders v1.36 ADAMTSL2 Zornitza Stark Gene: adamtsl2 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v1.36 ADAMTSL2 Zornitza Stark reviewed gene: ADAMTSL2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Dermatosparaxic Ehlers Danlos syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v1.36 ADAMTSL2 Sue White Classified gene: ADAMTSL2 as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v1.36 ADAMTSL2 Sue White Gene: adamtsl2 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v1.35 ADAMTSL2 Sue White gene: ADAMTSL2 was added
gene: ADAMTSL2 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: ADAMTSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ADAMTSL2 were set to 33369194; 26879370
Phenotypes for gene: ADAMTSL2 were set to Dermatosparaxic Ehlers Danlos syndrome
Penetrance for gene: ADAMTSL2 were set to unknown
Review for gene: ADAMTSL2 was set to AMBER
Added comment: Desai et al reported one family with a monoallelic variant in ADAMTSL2 (p. Gly421Ser) and features of Dermatosparaxic EDS (dEDS).
Steinle et al reported 5 unrelated individuals with the same missense variant in ADAMTSL2 (p. Gly421Ser) and connective tissue phenotype including generalized joint hypermobility and pain with fragility of internal and external tissues including of skin, dura, and arteries. Individuals had family history consistent with autosomal dominant inheritance.
No functional studies done. Variant is absent from GnomAD.
Sources: Literature
Aortopathy_Connective Tissue Disorders v1.34 IPO8 Zornitza Stark Publications for gene: IPO8 were set to
Aortopathy_Connective Tissue Disorders v1.33 IPO8 Zornitza Stark Classified gene: IPO8 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.33 IPO8 Zornitza Stark Gene: ipo8 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.32 IPO8 Zornitza Stark reviewed gene: IPO8: Rating: GREEN; Mode of pathogenicity: None; Publications: 34010604; Phenotypes: ; Mode of inheritance: None
Aortopathy_Connective Tissue Disorders v1.32 COL5A1 Zornitza Stark Phenotypes for gene: COL5A1 were changed from Ehlers-Danlos syndrome, classic type, 1, MIM# 130000 to Ehlers-Danlos syndrome, classic type, 1, MIM# 130000; Fibromuscular dysplasia, multifocal, MIM# 619329
Aortopathy_Connective Tissue Disorders v1.31 COL5A1 Zornitza Stark Publications for gene: COL5A1 were set to 30071989
Aortopathy_Connective Tissue Disorders v1.30 COL5A1 Zornitza Stark reviewed gene: COL5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32938213; Phenotypes: Fibromuscular dysplasia, multifocal, MIM# 619329; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v1.30 COL6A2 Zornitza Stark Phenotypes for gene: COL6A2 were changed from Bethlem myopathy 1 MIM #158810; Ullrich congenital muscular dystrophy 1 MIM #254090 to Myopathic EDS; Bethlem myopathy 1 MIM #158810; Ullrich congenital muscular dystrophy 1 MIM #254090
Aortopathy_Connective Tissue Disorders v1.29 COL6A2 Zornitza Stark Publications for gene: COL6A2 were set to (PMID: 29277723; 24443028)
Aortopathy_Connective Tissue Disorders v1.28 COL6A2 Zornitza Stark Classified gene: COL6A2 as Red List (low evidence)
Aortopathy_Connective Tissue Disorders v1.28 COL6A2 Zornitza Stark Gene: col6a2 has been classified as Red List (Low Evidence).
Aortopathy_Connective Tissue Disorders v1.27 COL6A2 Zornitza Stark reviewed gene: COL6A2: Rating: RED; Mode of pathogenicity: None; Publications: 31273343; Phenotypes: Myopathic EDS; Mode of inheritance: None
Aortopathy_Connective Tissue Disorders v1.27 EFEMP1 Zornitza Stark Phenotypes for gene: EFEMP1 were changed from EFEMP1-related connective tissue disorder to EFEMP1-related connective tissue disorder; cutis laxa
Aortopathy_Connective Tissue Disorders v1.26 EFEMP1 Zornitza Stark Publications for gene: EFEMP1 were set to 32006683; 31792352
Aortopathy_Connective Tissue Disorders v1.25 EFEMP1 Zornitza Stark Classified gene: EFEMP1 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.25 EFEMP1 Zornitza Stark Gene: efemp1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.24 EFEMP1 Zornitza Stark reviewed gene: EFEMP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33807164; Phenotypes: EFEMP1-related connective tissue disorder, cutis laxa; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Aortopathy_Connective Tissue Disorders v1.24 MFAP5 Zornitza Stark Phenotypes for gene: MFAP5 were changed from Aortic aneurysm, familial thoracic MIM# 616166 to Aortic aneurysm, familial thoracic MIM# 616166; MONDO:0014514
Aortopathy_Connective Tissue Disorders v1.23 MFAP5 Zornitza Stark Publications for gene: MFAP5 were set to 25434006; 30763214
Aortopathy_Connective Tissue Disorders v1.22 MFAP5 Michelle Torres reviewed gene: MFAP5: Rating: AMBER; Mode of pathogenicity: None; Publications: 33807627, 33514025, 29524629; Phenotypes: Aortic aneurysm, familial thoracic 9 (MIM#616166); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v1.22 FBN2 Zornitza Stark Publications for gene: FBN2 were set to
Aortopathy_Connective Tissue Disorders v1.21 FBN2 Zornitza Stark edited their review of gene: FBN2: Added comment: The association between mono-allelic variants in FBN2 and CCA is well established. Recent report of bi-allelic variants, Kloth (2021): biallelic FBN2 variants (PTC/missense) in a teenager with severe CCA, including cardiac defects, mild scoliosis and muscular involvement. Carrier parents both "healthy/unaffected". Phenotype matches mouse K/O. Authors performed a lit review and identified an additional 2 homozygous patients (both missense variants) with - fetal akinesia, brain ischemia and neonatal death - severe muscle weakness with bilateral clubfeet, a pronounced gait disturbance, recurrent patellar dislocations, flexion contractures, camptodactyly, widespread striae and an unusual myofibrillar disorganization, variation in fiber size and atrophic fibers in muscle biopsy.; Changed publications: 33571691
Aortopathy_Connective Tissue Disorders v1.21 FBN2 Zornitza Stark edited their review of gene: FBN2: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Aortopathy_Connective Tissue Disorders v1.21 FBN2 Zornitza Stark Mode of inheritance for gene: FBN2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Aortopathy_Connective Tissue Disorders v1.20 IPO8 Zornitza Stark Marked gene: IPO8 as ready
Aortopathy_Connective Tissue Disorders v1.20 IPO8 Zornitza Stark Gene: ipo8 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v1.20 IPO8 Zornitza Stark Phenotypes for gene: IPO8 were changed from to Loeys-Dietz syndrome-like; cardiovascular, neurologic, skeletal and immunologic abnormalities
Aortopathy_Connective Tissue Disorders v1.19 IPO8 Zornitza Stark Classified gene: IPO8 as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v1.19 IPO8 Zornitza Stark Gene: ipo8 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v1.18 IPO8 Sue White gene: IPO8 was added
gene: IPO8 was added to Aortopathy_Connective Tissue Disorders. Sources: Expert Review
Mode of inheritance for gene: IPO8 was set to BIALLELIC, autosomal or pseudoautosomal
Penetrance for gene: IPO8 were set to Complete
Review for gene: IPO8 was set to AMBER
Added comment: 12 individuals from 9 unrelated families in a cohort submitted for publication with bi-allelic IPO8 variants. Variants were nonsense/splice and some missense. Patients displayed a phenotype reminiscent of Loeys Dietz syndrome that variably combined cardiovascular, neurologic, skeletal and immunologic abnormalities along with dysmorphic features. Western blot on patient cells (4 individuals) showed reduced IPO8 expression. Disruption of IPO8 homologue in zebrafish associated with cardiac anomalies. Transcriptome analysis in zebrafish showed that IPO8-deficient zebrafish had abnormal TGFbeta pathway expression.
Sources: Expert Review
Aortopathy_Connective Tissue Disorders v1.17 HEY2 Zornitza Stark Marked gene: HEY2 as ready
Aortopathy_Connective Tissue Disorders v1.17 HEY2 Zornitza Stark Gene: hey2 has been classified as Red List (Low Evidence).
Aortopathy_Connective Tissue Disorders v1.17 HEY2 Chirag Patel gene: HEY2 was added
gene: HEY2 was added to Aortopathy_Connective Tissue Disorders. 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
Aortopathy_Connective Tissue Disorders v1.17 HEY2 Chirag Patel gene: HEY2 was added
gene: HEY2 was added to Aortopathy_Connective Tissue Disorders. 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
Aortopathy_Connective Tissue Disorders v1.16 Zornitza Stark removed gene:THSD4-AS1 from the panel
Aortopathy_Connective Tissue Disorders v1.15 THSD4 Chirag Patel Classified gene: THSD4 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.15 THSD4 Chirag Patel Gene: thsd4 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.14 THSD4 Chirag Patel Classified gene: THSD4 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.14 THSD4 Chirag Patel Gene: thsd4 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.13 THSD4 Chirag Patel gene: THSD4 was added
gene: THSD4 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: THSD4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: THSD4 were set to PMID: 32855533
Phenotypes for gene: THSD4 were set to Thoracic aortic aneurysm and dissection (TAAD)
Review for gene: THSD4 was set to GREEN
gene: THSD4 was marked as current diagnostic
Added comment: 5 functional heterozygous variants in THSD4 (two lead to a premature termination codon) found in 5 families with TAAD. Variants segregated with disease in other family members. THSD4 encodes ADAMTSL6, a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils. Thsd4+/- mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying a THSD4 variant and from Thsd4+/- mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix.
Sources: Literature
Aortopathy_Connective Tissue Disorders v1.12 THSD4-AS1 Chirag Patel Classified gene: THSD4-AS1 as Red List (low evidence)
Aortopathy_Connective Tissue Disorders v1.12 THSD4-AS1 Chirag Patel Gene: thsd4-as1 has been classified as Red List (Low Evidence).
Aortopathy_Connective Tissue Disorders v1.11 THSD4-AS1 Chirag Patel reviewed gene: THSD4-AS1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Aortopathy_Connective Tissue Disorders v1.11 THSD4-AS1 Chirag Patel Deleted their review
Aortopathy_Connective Tissue Disorders v1.11 THSD4-AS1 Chirag Patel Classified gene: THSD4-AS1 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.11 THSD4-AS1 Chirag Patel Gene: thsd4-as1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.11 THSD4-AS1 Chirag Patel Classified gene: THSD4-AS1 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v1.11 THSD4-AS1 Chirag Patel Gene: thsd4-as1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.10 THSD4-AS1 Chirag Patel gene: THSD4-AS1 was added
gene: THSD4-AS1 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: THSD4-AS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: THSD4-AS1 were set to PMID: 32855533
Phenotypes for gene: THSD4-AS1 were set to Thoracic aortic aneurysm and dissection (TAAD)
Review for gene: THSD4-AS1 was set to GREEN
gene: THSD4-AS1 was marked as current diagnostic
Added comment: 5 functional heterozygous variants in THSD4 (two lead to a premature termination codon) found in 5 families with TAAD. Variants segregated with disease in other family members. THSD4 encodes ADAMTSL6, a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils. Thsd4+/- mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying a THSD4 variant and from Thsd4+/- mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix.
Sources: Literature
Aortopathy_Connective Tissue Disorders v1.9 SLC2A10 Zornitza Stark Phenotypes for gene: SLC2A10 were changed from Arterial tortuosity syndrome MIM#606145 to Arterial tortuosity syndrome MIM#208050
Aortopathy_Connective Tissue Disorders v1.8 SLC2A10 Zornitza Stark reviewed gene: SLC2A10: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Arterial tortuosity syndrome MIM#208050; Mode of inheritance: None
Aortopathy_Connective Tissue Disorders v1.8 SKI Zornitza Stark Phenotypes for gene: SKI were changed from Shprintzen-Goldberg syndrome, MIM#164780 to Shprintzen-Goldberg syndrome, MIM#182212
Aortopathy_Connective Tissue Disorders v1.7 SKI Zornitza Stark edited their review of gene: SKI: Changed rating: GREEN; Changed phenotypes: Shprintzen-Goldberg syndrome, MIM#182212
Aortopathy_Connective Tissue Disorders v1.7 PRKG1 Zornitza Stark Phenotypes for gene: PRKG1 were changed from Aortic aneurysm, familial thoracic 8, MIM#176894 to Aortic aneurysm, familial thoracic 8, MIM#615436
Aortopathy_Connective Tissue Disorders v1.6 PRKG1 Zornitza Stark reviewed gene: PRKG1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Aortic aneurysm, familial thoracic 8, MIM#615436; Mode of inheritance: None
Aortopathy_Connective Tissue Disorders v1.6 PCGF2 Zornitza Stark Phenotypes for gene: PCGF2 were changed from Turnpenny-Fry syndrome, MIM#600346 to Turnpenny-Fry syndrome, MIM#618371
Aortopathy_Connective Tissue Disorders v1.5 PCGF2 Zornitza Stark edited their review of gene: PCGF2: Changed phenotypes: Turnpenny-Fry syndrome, MIM#618371
Aortopathy_Connective Tissue Disorders v1.5 MYLK Zornitza Stark Phenotypes for gene: MYLK were changed from Aortic aneurysm, familial thoracic 7, MIM#600922 to Aortic aneurysm, familial thoracic 7, MIM#613780
Aortopathy_Connective Tissue Disorders v1.4 MYLK Zornitza Stark reviewed gene: MYLK: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Aortic aneurysm, familial thoracic 7, MIM#613780; Mode of inheritance: None
Aortopathy_Connective Tissue Disorders v1.4 COL5A2 Zornitza Stark Phenotypes for gene: COL5A2 were changed from Ehlers-Danlos syndrome, classic type, 2, MIM#120190 to Ehlers-Danlos syndrome, classic type, 2, MIM#130010
Aortopathy_Connective Tissue Disorders v1.3 COL5A2 Zornitza Stark edited their review of gene: COL5A2: Changed rating: GREEN
Aortopathy_Connective Tissue Disorders v1.3 COL5A2 Zornitza Stark reviewed gene: COL5A2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Ehlers-Danlos syndrome, classic type, 2, MIM#130010; Mode of inheritance: None
Aortopathy_Connective Tissue Disorders v1.3 ATP6V1E1 Zornitza Stark Marked gene: ATP6V1E1 as ready
Aortopathy_Connective Tissue Disorders v1.3 ATP6V1E1 Zornitza Stark Gene: atp6v1e1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v1.3 PI4K2A Zornitza Stark Marked gene: PI4K2A as ready
Aortopathy_Connective Tissue Disorders v1.3 PI4K2A Zornitza Stark Gene: pi4k2a has been classified as Red List (Low Evidence).
Aortopathy_Connective Tissue Disorders v1.3 PI4K2A Zornitza Stark gene: PI4K2A was added
gene: PI4K2A was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: PI4K2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PI4K2A were set to 32418222
Phenotypes for gene: PI4K2A were set to Cutis laxa, intellectual disability, movement disorder
Review for gene: PI4K2A was set to RED
Added comment: Single individual reported with homozygous missense variant and functional data including mouse model.
Sources: Literature
Aortopathy_Connective Tissue Disorders v1.2 ZNF469 Zornitza Stark Phenotypes for gene: ZNF469 were changed from Brittle cornea syndrome 1 to Brittle cornea syndrome 1,MIM# 229200
Aortopathy_Connective Tissue Disorders v1.1 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
Aortopathy_Connective Tissue Disorders v1.0 ROBO4 Zornitza Stark edited their review of gene: ROBO4: Added comment: Two families plus segregation and functional data including animal model.; Changed publications: 30455415
Aortopathy_Connective Tissue Disorders v1.0 ROBO4 Zornitza Stark reviewed gene: ROBO4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Aortic valve disease 8, MIM# 618496; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v1.0 Zornitza Stark promoted panel to version 1.0
Aortopathy_Connective Tissue Disorders v0.162 MAPK8 Zornitza Stark Marked gene: MAPK8 as ready
Aortopathy_Connective Tissue Disorders v0.162 MAPK8 Zornitza Stark Gene: mapk8 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.162 MAPK8 Zornitza Stark Classified gene: MAPK8 as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v0.162 MAPK8 Zornitza Stark Gene: mapk8 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.161 MAPK8 Zornitza Stark gene: MAPK8 was added
gene: MAPK8 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: MAPK8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAPK8 were set to 31784499
Phenotypes for gene: MAPK8 were set to Chronic mucocutaneous candidiasis; Connective tissue disorders
Review for gene: MAPK8 was set to AMBER
Added comment: PMID: 31784499 (2020) - Three cases in a single family with chronic mucocutaneous candidiasis and a connective tissue disorder that clinically overlaps with hEDS. WES revealed a splice-site variant (c.311+1G>A) in the MAPK8 gene that segregated with the disorder. Includes supportive functional data using patient-derived fibroblasts, showing that the variant impairs IL-17A/F immunity and the development of Th17 cells.

Single family with high level of supportive functional data.
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.160 PTDSS1 Zornitza Stark Marked gene: PTDSS1 as ready
Aortopathy_Connective Tissue Disorders v0.160 PTDSS1 Zornitza Stark Gene: ptdss1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.160 PTDSS1 Bryony Thompson Classified gene: PTDSS1 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.160 PTDSS1 Bryony Thompson Gene: ptdss1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.159 PTDSS1 Bryony Thompson gene: PTDSS1 was added
gene: PTDSS1 was added to Aortopathy_Connective Tissue Disorders. Sources: Expert list
Mode of inheritance for gene: PTDSS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTDSS1 were set to 24241535; 29341480; 31403251
Phenotypes for gene: PTDSS1 were set to Lenz-Majewski hyperostotic dwarfism MIM#151050
Mode of pathogenicity for gene: PTDSS1 was set to Other
Review for gene: PTDSS1 was set to GREEN
Added comment: 9 unrelated patients with cutis laxa as a prominent feature of a syndromic phenotype, with 5 different de novo (or assumed de novo) heterozygous missense mutations. Gain-of-function is the established or expected mechanism of disease for these variants.
Sources: Expert list
Aortopathy_Connective Tissue Disorders v0.158 ATP6V1E1 Bryony Thompson Classified gene: ATP6V1E1 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.158 ATP6V1E1 Bryony Thompson Gene: atp6v1e1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.157 ATP6V1E1 Bryony Thompson gene: ATP6V1E1 was added
gene: ATP6V1E1 was added to Aortopathy_Connective Tissue Disorders. Sources: Expert list
Mode of inheritance for gene: ATP6V1E1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP6V1E1 were set to 28065471; 27023906
Phenotypes for gene: ATP6V1E1 were set to Cutis laxa, autosomal recessive, type IIC MIM#617402
Review for gene: ATP6V1E1 was set to GREEN
Added comment: 3 unrelated consanguineous families from Iran, Kuwait, and Saudi Arabia, homozygous for 2 different missense variants (L128P, R212W) with paediatric onset cutis laxa, each segregating in an affected sibling. Molecular analyses of patient tissues was supportive: complexome profiling in cultured fibroblasts showed a markedly reduced abundance of the assembled V1 domain and of the complete membrane-bound V1V0 complex.
Sources: Expert list
Aortopathy_Connective Tissue Disorders v0.156 MAT2A Bryony Thompson Marked gene: MAT2A as ready
Aortopathy_Connective Tissue Disorders v0.156 MAT2A Bryony Thompson Gene: mat2a has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.156 MAT2A Bryony Thompson Classified gene: MAT2A as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v0.156 MAT2A Bryony Thompson Gene: mat2a has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.155 MAT2A Bryony Thompson gene: MAT2A was added
gene: MAT2A was added to Aortopathy_Connective Tissue Disorders. Sources: ClinGen
Mode of inheritance for gene: MAT2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAT2A were set to 30071989; 25557781
Phenotypes for gene: MAT2A were set to Thoracic aortic aneurysm
Review for gene: MAT2A was set to AMBER
Added comment: PMID: 25557781 - A rare missense (p.Glu344Ala) identified in a family that segregated with thoracic aortic disease and a second missense was identified in an unrelated thoracic aortic disease proband. Morpholino KO in zebrafish lead to pericardial edema and rescue by human MAT2A
PMID: 30071989 - Classified as Limited by the HTAAD GCEP, downgraded from Moderate due to the absence of additional variants identified in a large (>400) unpublished aortopathy cohort. Categorised as uncertain, because it is a recently reported gene-disease association.
Sources: ClinGen
Aortopathy_Connective Tissue Disorders v0.154 HCN4 Bryony Thompson Marked gene: HCN4 as ready
Aortopathy_Connective Tissue Disorders v0.154 HCN4 Bryony Thompson Gene: hcn4 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.154 HCN4 Bryony Thompson Classified gene: HCN4 as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v0.154 HCN4 Bryony Thompson Gene: hcn4 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.153 HCN4 Bryony Thompson gene: HCN4 was added
gene: HCN4 was added to Aortopathy_Connective Tissue Disorders. Sources: ClinGen
Mode of inheritance for gene: HCN4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HCN4 were set to 30071989; 27173043
Phenotypes for gene: HCN4 were set to Sick sinus syndrome 2 with cardiac noncompaction and ascending aorta dilation
Review for gene: HCN4 was set to AMBER
Added comment: PMID: 27173043 - Dilation of the ascending aorta was detected in 20 of 26 (77%) HCN4 mutation-positive cases from 7 unrelated families in whom images could be obtained to assess the ascending aorta.
PMID: 30071989 - Classified as Limited by the HTAAD GCEP, downgraded from Moderate due to the absence of aortic dissection and lack of longitudinal data on aortic growth. Categorised as uncertain, because it is a recently reported gene-disease association.
Sources: ClinGen
Aortopathy_Connective Tissue Disorders v0.150 ATP6V1A Zornitza Stark Classified gene: ATP6V1A as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v0.150 ATP6V1A Zornitza Stark Gene: atp6v1a has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.149 ATP6V1A Zornitza Stark reviewed gene: ATP6V1A: Rating: AMBER; Mode of pathogenicity: None; Publications: 28065471; Phenotypes: Cutis laxa, autosomal recessive, type IID, MIM# 617403; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Aortopathy_Connective Tissue Disorders v0.149 PYCR1 Zornitza Stark Marked gene: PYCR1 as ready
Aortopathy_Connective Tissue Disorders v0.149 PYCR1 Zornitza Stark Gene: pycr1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.149 PYCR1 Zornitza Stark Phenotypes for gene: PYCR1 were changed from to Cutis laxa, autosomal recessive, type IIB, MIM# 612940; Cutis laxa, autosomal recessive, type IIIB, MIM# 614438
Aortopathy_Connective Tissue Disorders v0.148 PYCR1 Zornitza Stark Classified gene: PYCR1 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.148 PYCR1 Zornitza Stark Gene: pycr1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.147 PYCR1 Dean Phelan gene: PYCR1 was added
gene: PYCR1 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: PYCR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PYCR1 were set to PMID: 19648921; 4076251; 22052856; 19576563; 19648921; 9648921; 22052856; 28294978; 27756598
Review for gene: PYCR1 was set to GREEN
gene: PYCR1 was marked as current diagnostic
Added comment: Variants in this gene are associated with Cutis Laxa:
Cutis laxa type 2 (ARCL2, [MIM 219200]) is an autosomal-recessive multisystem disorder with prominent connective-tissue features characterized by the appearance of premature aging, particularly wrinkled and lax skin with reduced elasticity.

GEL PanelApp: Green in EDS panel - clinical features overlapping EDS
Cutis laxa, autosomal recessive, type IIIB (ARCL3B) PMID: 19648921,4076251, 22052856
Cutis laxa, autosomal recessive, type IIB (ARCL2B) PMID: 19576563, 19648921, 9648921, 22052856, 28294978 AR

PMID: 27756598: a homozygous mutation in PYCR1 segregating in the family with the affected individuals with complex connective tissue disorder and severe intellectual disability.
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.147 PIEZO2 Zornitza Stark Marked gene: PIEZO2 as ready
Aortopathy_Connective Tissue Disorders v0.147 PIEZO2 Zornitza Stark Gene: piezo2 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.147 PIEZO2 Zornitza Stark Classified gene: PIEZO2 as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v0.147 PIEZO2 Zornitza Stark Gene: piezo2 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.146 RIN2 Zornitza Stark Marked gene: RIN2 as ready
Aortopathy_Connective Tissue Disorders v0.146 RIN2 Zornitza Stark Gene: rin2 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.146 RIN2 Zornitza Stark Classified gene: RIN2 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.146 RIN2 Zornitza Stark Gene: rin2 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.145 COL6A2 Seb Lunke Marked gene: COL6A2 as ready
Aortopathy_Connective Tissue Disorders v0.145 COL6A2 Seb Lunke Gene: col6a2 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.145 COL6A3 Zornitza Stark Marked gene: COL6A3 as ready
Aortopathy_Connective Tissue Disorders v0.145 COL6A3 Zornitza Stark Gene: col6a3 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.145 COL6A3 Zornitza Stark Classified gene: COL6A3 as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v0.145 COL6A3 Zornitza Stark Gene: col6a3 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.144 COL6A2 Seb Lunke Classified gene: COL6A2 as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v0.144 COL6A2 Seb Lunke Gene: col6a2 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.143 COL6A3 Zornitza Stark reviewed gene: COL6A3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Aortopathy_Connective Tissue Disorders v0.143 COL6A2 Seb Lunke reviewed gene: COL6A2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Aortopathy_Connective Tissue Disorders v0.143 LTBP4 Zornitza Stark Marked gene: LTBP4 as ready
Aortopathy_Connective Tissue Disorders v0.143 LTBP4 Zornitza Stark Gene: ltbp4 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.143 LTBP4 Zornitza Stark Classified gene: LTBP4 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.143 LTBP4 Zornitza Stark Gene: ltbp4 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.142 GORAB Zornitza Stark Marked gene: GORAB as ready
Aortopathy_Connective Tissue Disorders v0.142 GORAB Zornitza Stark Gene: gorab has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.142 GORAB Zornitza Stark Classified gene: GORAB as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v0.142 GORAB Zornitza Stark Gene: gorab has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.141 COL6A1 Zornitza Stark Marked gene: COL6A1 as ready
Aortopathy_Connective Tissue Disorders v0.141 COL6A1 Zornitza Stark Gene: col6a1 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.141 COL6A1 Zornitza Stark Classified gene: COL6A1 as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v0.141 COL6A1 Zornitza Stark Gene: col6a1 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.140 COL6A1 Zornitza Stark reviewed gene: COL6A1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Aortopathy_Connective Tissue Disorders v0.140 ATP6V1A Zornitza Stark Marked gene: ATP6V1A as ready
Aortopathy_Connective Tissue Disorders v0.140 ATP6V1A Zornitza Stark Gene: atp6v1a has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.140 ATP6V1A Zornitza Stark Classified gene: ATP6V1A as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.140 ATP6V1A Zornitza Stark Gene: atp6v1a has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.139 P4HA1 Zornitza Stark Marked gene: P4HA1 as ready
Aortopathy_Connective Tissue Disorders v0.139 P4HA1 Zornitza Stark Gene: p4ha1 has been classified as Red List (Low Evidence).
Aortopathy_Connective Tissue Disorders v0.139 P4HA1 Zornitza Stark gene: P4HA1 was added
gene: P4HA1 was added to Aortopathy_Connective Tissue Disorders. Sources: Expert list
Mode of inheritance for gene: P4HA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: P4HA1 were set to 28419360
Phenotypes for gene: P4HA1 were set to Joint hypermobility; Contractures; Hypotonia; Mild skeletal dysplasia without bone fragility; High myopia
Review for gene: P4HA1 was set to RED
Added comment: Single family reported with two affected individuals.
Sources: Expert list
Aortopathy_Connective Tissue Disorders v0.138 GORAB Paul De Fazio changed review comment from: 13 families described with biallelic LoF variants (PMID: 18997784). Phenotypes included wrinkly skin and osteoporosis.

One more individual described with a homozygous missense variant (PMID: 19681135). Clinical diagnosis of GO was based on the presence of typical facial features, reduced skin elasticity, and decreased bone density.

There have been no clinical reports since 2009.

This gene is Green in PanelApp England because it has phenotypic overlap with Eherls Danlos syndrome. I have left it amber as I'm not sure if the overlap is sufficient for this panel.

From OMIM: "Geroderma osteodysplasticum (GO) is an autosomal recessive disorder characterized by skin wrinkling limited to the dorsa of hands and feet and to the abdomen, bowed long bones, and osteopenia with frequent fractures. There is a distinctive facial appearance with droopy skin at the cheeks, maxillary hypoplasia, and large ears. Adult patients appear prematurely aged"
Sources: Literature; to: 13 families described with biallelic LoF variants (PMID: 18997784). Phenotypes included wrinkly skin and osteoporosis.

One more individual described with a homozygous missense variant (PMID: 19681135). Clinical diagnosis of GO was based on the presence of typical facial features, reduced skin elasticity, and decreased bone density.

There have been no clinical reports since 2009.

This gene is Green in PanelApp England EDS panel because it has phenotypic overlap with Eherls Danlos syndrome. I have left it amber as I'm not sure if the overlap is sufficient for this panel.

From OMIM: "Geroderma osteodysplasticum (GO) is an autosomal recessive disorder characterized by skin wrinkling limited to the dorsa of hands and feet and to the abdomen, bowed long bones, and osteopenia with frequent fractures. There is a distinctive facial appearance with droopy skin at the cheeks, maxillary hypoplasia, and large ears. Adult patients appear prematurely aged"
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.138 GORAB Paul De Fazio changed review comment from: 13 families described with biallelic LoF variants (PMID: 18997784). Phenotypes included wrinkly skin and osteoporosis.

One more individual described with a homozygous missense variant (PMID: 19681135). Clinical diagnosis of GO was based on the presence of typical facial features, reduced skin elasticity, and decreased bone density.

There have been no clinical reports since 2009.

This gene is Green in PanelApp England because it has phenotypic overlap with Eherls Danlos syndrome.

From OMIM: "Geroderma osteodysplasticum (GO) is an autosomal recessive disorder characterized by skin wrinkling limited to the dorsa of hands and feet and to the abdomen, bowed long bones, and osteopenia with frequent fractures. There is a distinctive facial appearance with droopy skin at the cheeks, maxillary hypoplasia, and large ears. Adult patients appear prematurely aged"
Sources: Literature; to: 13 families described with biallelic LoF variants (PMID: 18997784). Phenotypes included wrinkly skin and osteoporosis.

One more individual described with a homozygous missense variant (PMID: 19681135). Clinical diagnosis of GO was based on the presence of typical facial features, reduced skin elasticity, and decreased bone density.

There have been no clinical reports since 2009.

This gene is Green in PanelApp England because it has phenotypic overlap with Eherls Danlos syndrome. I have left it amber as I'm not sure if the overlap is sufficient for this panel.

From OMIM: "Geroderma osteodysplasticum (GO) is an autosomal recessive disorder characterized by skin wrinkling limited to the dorsa of hands and feet and to the abdomen, bowed long bones, and osteopenia with frequent fractures. There is a distinctive facial appearance with droopy skin at the cheeks, maxillary hypoplasia, and large ears. Adult patients appear prematurely aged"
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.138 GORAB Paul De Fazio changed review comment from: 13 families described with biallelic LoF variants (PMID: 18997784). Phenotypes included wrinkly skin and osteoporosis.

One more individual described with a homozygous missense variant (PMID: 19681135). Clinical diagnosis of GO was based on the presence of typical facial features, reduced skin elasticity, and decreased bone density.

There have been no clinical reports since 2009.

This gene is Green in PanelApp England because it has phenotypic overlap with Eherls Danlos syndrome.
Sources: Literature; to: 13 families described with biallelic LoF variants (PMID: 18997784). Phenotypes included wrinkly skin and osteoporosis.

One more individual described with a homozygous missense variant (PMID: 19681135). Clinical diagnosis of GO was based on the presence of typical facial features, reduced skin elasticity, and decreased bone density.

There have been no clinical reports since 2009.

This gene is Green in PanelApp England because it has phenotypic overlap with Eherls Danlos syndrome.

From OMIM: "Geroderma osteodysplasticum (GO) is an autosomal recessive disorder characterized by skin wrinkling limited to the dorsa of hands and feet and to the abdomen, bowed long bones, and osteopenia with frequent fractures. There is a distinctive facial appearance with droopy skin at the cheeks, maxillary hypoplasia, and large ears. Adult patients appear prematurely aged"
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.138 PIEZO2 Paul De Fazio changed review comment from: 1 individual diagnosed with Marden-Walker syndrome was described with a de novo missense variant in this gene (PMID: 24726473). This is the only literature supporting this gene-disease association. One other proband with MWS did not have a variant in this gene.

The same study reported that another 10 families/individuals with Gordon syndrome (distal arthrogryposis type 3) and 24 with distal atrogryposis type 5 had variants in this gene. The authors posit that these three conditions represent a spectrum of disease.

Marden-Walker syndrome is described as a connective tissue disorder (https://rarediseases.info.nih.gov/diseases/6973/marden-walker-syndrome) and has significant overlap with other multi-system congenital contracture syndromes including D4ST1-Deficient Ehlers-Danlos syndrome (adducted thumb-clubfoot syndrome) (PMID: 27375131). GEL has this gene as Amber in the EDS panel noting some overlap with Kyphoscoliotic EDS in terms of scoliosis.
Sources: Literature; to: 1 individual diagnosed with Marden-Walker syndrome was described with a de novo missense variant in this gene (PMID: 24726473). This is the only literature supporting this gene-disease association. One other proband with MWS did not have a variant in this gene although the authors note that their sequencing strategy would not have been able to detect some indels including single-exon deletions.

The same study reported that another 10 families/individuals with Gordon syndrome (distal arthrogryposis type 3) and 24 with distal atrogryposis type 5 had variants in this gene. The authors posit that these three conditions represent a spectrum of disease.

Marden-Walker syndrome is described as a connective tissue disorder (https://rarediseases.info.nih.gov/diseases/6973/marden-walker-syndrome) and has significant overlap with other multi-system congenital contracture syndromes including D4ST1-Deficient Ehlers-Danlos syndrome (adducted thumb-clubfoot syndrome) (PMID: 27375131). GEL has this gene as Amber in the EDS panel noting some overlap with Kyphoscoliotic EDS in terms of scoliosis.
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.138 PIEZO2 Paul De Fazio changed review comment from: 1 individual diagnosed with Marden-Walker syndrome was described with a de novo missense variant in this gene (PMID: 24726473). Another 10 families/individuals with Gordon syndrome (distal arthrogryposis type 3) and 24 with distal atrogryposis type 5 had variants in this gene. The authors posit that these three conditions represent a spectrum of disease.

Marden-Walker syndrome is described as a connective tissue disorder (https://rarediseases.info.nih.gov/diseases/6973/marden-walker-syndrome) and has significant overlap with other multi-system congenital contracture syndromes including D4ST1-Deficient Ehlers-Danlos syndrome (adducted thumb-clubfoot syndrome) (PMID: 27375131). GEL has this gene as Amber in the EDS panel noting some overlap with Kyphoscoliotic EDS in terms of scoliosis.
Sources: Literature; to: 1 individual diagnosed with Marden-Walker syndrome was described with a de novo missense variant in this gene (PMID: 24726473). This is the only literature supporting this gene-disease association. One other proband with MWS did not have a variant in this gene.

The same study reported that another 10 families/individuals with Gordon syndrome (distal arthrogryposis type 3) and 24 with distal atrogryposis type 5 had variants in this gene. The authors posit that these three conditions represent a spectrum of disease.

Marden-Walker syndrome is described as a connective tissue disorder (https://rarediseases.info.nih.gov/diseases/6973/marden-walker-syndrome) and has significant overlap with other multi-system congenital contracture syndromes including D4ST1-Deficient Ehlers-Danlos syndrome (adducted thumb-clubfoot syndrome) (PMID: 27375131). GEL has this gene as Amber in the EDS panel noting some overlap with Kyphoscoliotic EDS in terms of scoliosis.
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.138 PIEZO2 Paul De Fazio edited their review of gene: PIEZO2: Changed publications: 24726473, 27375131
Aortopathy_Connective Tissue Disorders v0.138 PIEZO2 Paul De Fazio changed review comment from: 1 individual diagnosed with Marden-Walker syndrome was described with a de novo missense variant in this gene (PMID: 24726473). Another 10 families/individuals with Gordon syndrome (distal arthrogryposis type 3) and 24 with distal atrogryposis type 5 had variants in this gene. The authors posit that these three conditions represent a spectrum of disease.

Marden-Walker syndrome is described as a connective tissue disorder (https://rarediseases.info.nih.gov/diseases/6973/marden-walker-syndrome) and has significant overlap with other multi-system congenital contracture syndromes including D4ST1-Deficient Ehlers-Danlos syndrome (adducted thumb-clubfoot syndrome). GEL has this gene as Amber in the EDS panel noting some overlap with Kyphoscoliotic EDS in terms of scoliosis.
Sources: Literature; to: 1 individual diagnosed with Marden-Walker syndrome was described with a de novo missense variant in this gene (PMID: 24726473). Another 10 families/individuals with Gordon syndrome (distal arthrogryposis type 3) and 24 with distal atrogryposis type 5 had variants in this gene. The authors posit that these three conditions represent a spectrum of disease.

Marden-Walker syndrome is described as a connective tissue disorder (https://rarediseases.info.nih.gov/diseases/6973/marden-walker-syndrome) and has significant overlap with other multi-system congenital contracture syndromes including D4ST1-Deficient Ehlers-Danlos syndrome (adducted thumb-clubfoot syndrome) (PMID: 27375131). GEL has this gene as Amber in the EDS panel noting some overlap with Kyphoscoliotic EDS in terms of scoliosis.
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.138 PIEZO2 Paul De Fazio gene: PIEZO2 was added
gene: PIEZO2 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: PIEZO2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIEZO2 were set to 24726473
Phenotypes for gene: PIEZO2 were set to Marden-Walker syndrome (MIM#248700); Arthrogryposis, distal, type 3 (MIM#114300); Arthrogryposis, distal, type 5 (MIM#108145)
Review for gene: PIEZO2 was set to AMBER
gene: PIEZO2 was marked as current diagnostic
Added comment: 1 individual diagnosed with Marden-Walker syndrome was described with a de novo missense variant in this gene (PMID: 24726473). Another 10 families/individuals with Gordon syndrome (distal arthrogryposis type 3) and 24 with distal atrogryposis type 5 had variants in this gene. The authors posit that these three conditions represent a spectrum of disease.

Marden-Walker syndrome is described as a connective tissue disorder (https://rarediseases.info.nih.gov/diseases/6973/marden-walker-syndrome) and has significant overlap with other multi-system congenital contracture syndromes including D4ST1-Deficient Ehlers-Danlos syndrome (adducted thumb-clubfoot syndrome). GEL has this gene as Amber in the EDS panel noting some overlap with Kyphoscoliotic EDS in terms of scoliosis.
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.138 RIN2 Ain Roesley gene: RIN2 was added
gene: RIN2 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: RIN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RIN2 were set to 19631308; 20424861; 23963297; 24449201
Phenotypes for gene: RIN2 were set to Macrocephaly, alopecia, cutis laxa, and scoliosis (MIM# 613075)
Penetrance for gene: RIN2 were set to unknown
Review for gene: RIN2 was set to GREEN
Added comment: Also known as MACS syndrome. The most striking clinical features include macrocephaly, progressive facial coarsening, gingival hypertrophy, severe scoliosis, sparse hair and skin and joint hyperlaxity. All families reported thus far are homozygous for PTVs

PMID: 19631308; 1x large consanguineous kindred with 3 affecteds

PMID: 20424861; 1x consanguineous Algerian family with three affected siblings.

PMID: 23963297; 1x patient with MACS syndrome and an additional phenotype of periventricular cystic lesions

PMID: 24449201; 2 sibs born to non-consanguineous Turkish parents exhibiting additional clinical features of bronchiectasis and hypergonadotropic hypogonadism.
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.138 LTBP4 Ain Roesley edited their review of gene: LTBP4: Changed publications: 22829427; Changed phenotypes: Cutis laxa, autosomal recessive, type IC (MIM# 613177)
Aortopathy_Connective Tissue Disorders v0.138 ATP6V1A Ain Roesley edited their review of gene: ATP6V1A: Changed publications: 28065471
Aortopathy_Connective Tissue Disorders v0.138 COL6A3 Naomi Baker gene: COL6A3 was added
gene: COL6A3 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: COL6A3 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: COL6A3 were set to PMID: 29277723; 24443028.
Phenotypes for gene: COL6A3 were set to Bethlem myopathy 1 MIM #158810; Ullrich congenital muscular dystrophy 1 MIM #254090
Penetrance for gene: COL6A3 were set to Complete
Mode of pathogenicity for gene: COL6A3 was set to Other
Review for gene: COL6A3 was set to GREEN
Added comment: Both loss-of-function and dominant negative mechanism has been reported for this gene. Mutations result in a spectrum of disease, ranging from the milder Bethlem myopathy (monoallelic) to the more severe Ullrich congenital muscular dystrophy (biallelic) (PMID: 29277723; 24443028).
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.138 COL6A2 Naomi Baker gene: COL6A2 was added
gene: COL6A2 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: COL6A2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: COL6A2 were set to (PMID: 29277723; 24443028)
Phenotypes for gene: COL6A2 were set to Bethlem myopathy 1 MIM #158810; Ullrich congenital muscular dystrophy 1 MIM #254090
Penetrance for gene: COL6A2 were set to Complete
Mode of pathogenicity for gene: COL6A2 was set to Other
Review for gene: COL6A2 was set to GREEN
Added comment: Both loss-of-function and dominant negative mechanism has been reported for this gene. Mutations result in a spectrum of disease, ranging from the milder Bethlem myopathy (monoallelic) to the more severe Ullrich congenital muscular dystrophy (biallelic) (PMID: 29277723; 24443028).
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.138 LTBP4 Ain Roesley gene: LTBP4 was added
gene: LTBP4 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: LTBP4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LTBP4 were set to PMID: 22829427
Phenotypes for gene: LTBP4 were set to Cutis laxa, autosomal recessive, type IC (MIM# 613177)
Penetrance for gene: LTBP4 were set to unknown
Review for gene: LTBP4 was set to GREEN
Added comment: PMID: 22829427;
- 9 families with cutis laxa, either homozygotes or cHets.
- all PTVs except 1 homozygous missense
- Most LTBP4 mutation positive patients (11/13) had generalized moderate to severe cutis laxa, skin was hyperextensible, or appeared translucent with a prominent venous pattern (3/9), few patients had thin and slowly growing hair and inguinal and diaphragmatic hernias (5/9)
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.138 GORAB Paul De Fazio gene: GORAB was added
gene: GORAB was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: GORAB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GORAB were set to 18997784; 19681135
Phenotypes for gene: GORAB were set to Geroderma osteodysplasticum MIM#231070
Review for gene: GORAB was set to AMBER
gene: GORAB was marked as current diagnostic
Added comment: 13 families described with biallelic LoF variants (PMID: 18997784). Phenotypes included wrinkly skin and osteoporosis.

One more individual described with a homozygous missense variant (PMID: 19681135). Clinical diagnosis of GO was based on the presence of typical facial features, reduced skin elasticity, and decreased bone density.

There have been no clinical reports since 2009.

This gene is Green in PanelApp England because it has phenotypic overlap with Eherls Danlos syndrome.
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.138 COL6A1 Naomi Baker gene: COL6A1 was added
gene: COL6A1 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: COL6A1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: COL6A1 were set to PMID: 29277723; 24443028.
Phenotypes for gene: COL6A1 were set to Bethlem myopathy 1 MIM #158810; Ullrich congenital muscular dystrophy 1 MIM #254090
Penetrance for gene: COL6A1 were set to Complete
Mode of pathogenicity for gene: COL6A1 was set to Other
Review for gene: COL6A1 was set to GREEN
Added comment: Both loss-of-function and dominant negative mechanism has been reported for this gene. Mutations result in a spectrum of disease, ranging from the milder Bethlem myopathy (monoallelic) to the more severe Ullrich congenital muscular dystrophy (biallelic) (PMID: 29277723; 24443028).
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.138 ATP6V1A Ain Roesley gene: ATP6V1A was added
gene: ATP6V1A was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: ATP6V1A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP6V1A were set to PMID: 28065471
Phenotypes for gene: ATP6V1A were set to Cutis laxa, autosomal recessive, type IID (MIM# 617403)
Penetrance for gene: ATP6V1A were set to unknown
Review for gene: ATP6V1A was set to GREEN
Added comment: PMID: 28065471;
- 3 families (including 2 consanguineous) with homozygous missense
- in vitro assays using patients' fibroblasts demonstrated the variants disrupted V-ATPase complex assembly and stability
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.138 Zornitza Stark removed gene:ACVR1 from the panel
Aortopathy_Connective Tissue Disorders v0.137 FOXE3 Zornitza Stark Marked gene: FOXE3 as ready
Aortopathy_Connective Tissue Disorders v0.137 FOXE3 Zornitza Stark Gene: foxe3 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.137 FOXE3 Zornitza Stark Phenotypes for gene: FOXE3 were changed from to {Aortic aneurysm, familial thoracic 11, susceptibility to}, MIM# 617349
Aortopathy_Connective Tissue Disorders v0.136 FOXE3 Zornitza Stark Classified gene: FOXE3 as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v0.136 FOXE3 Zornitza Stark Gene: foxe3 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.135 COL12A1 Bryony Thompson Marked gene: COL12A1 as ready
Aortopathy_Connective Tissue Disorders v0.135 COL12A1 Bryony Thompson Gene: col12a1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.135 COL12A1 Bryony Thompson Classified gene: COL12A1 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.135 COL12A1 Bryony Thompson Gene: col12a1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.134 COL12A1 Bryony Thompson gene: COL12A1 was added
gene: COL12A1 was added to Aortopathy_Connective Tissue Disorders. Sources: Expert list
Mode of inheritance for gene: COL12A1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: COL12A1 were set to 28306229; 31273343; 24334604
Phenotypes for gene: COL12A1 were set to Myopathic EDS; Bethlem myopathy 2 MIM#616471; Ullrich congenital muscular dystrophy 2 MIM#616470
Review for gene: COL12A1 was set to GREEN
Added comment: One of the 19 EDS genes recognised by the International EDS Consortium (PMID: 28306229).
18 cases from 12 unrelated families have been reported with monoallelic variants (both de novo and inherited), and one family has been reported with a homozygous variant. A null mouse model recapitulates the phenotype.
Sources: Expert list
Aortopathy_Connective Tissue Disorders v0.133 COL1A2 Bryony Thompson Marked gene: COL1A2 as ready
Aortopathy_Connective Tissue Disorders v0.133 COL1A2 Bryony Thompson Gene: col1a2 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.133 COL1A2 Bryony Thompson Classified gene: COL1A2 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.133 COL1A2 Bryony Thompson Gene: col1a2 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.132 COL1A2 Bryony Thompson gene: COL1A2 was added
gene: COL1A2 was added to Aortopathy_Connective Tissue Disorders. Sources: Expert list
Mode of inheritance for gene: COL1A2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: COL1A2 were set to 28306229; 32091183; 2993307; 30821104
Phenotypes for gene: COL1A2 were set to Ehlers-Danlos syndrome, arthrochalasia type, 2 MIM#617821; Ehlers-Danlos syndrome, cardiac valvular type MIM#225320
Review for gene: COL1A2 was set to GREEN
gene: COL1A2 was marked as current diagnostic
Added comment: One of the 19 EDS genes recognised by the International EDS Consortium (PMID: 28306229). Monoallelic variants leading to (partial) loss of exon 6 are a well-established cause arthrochalasia type EDS.
Biallelic variant that lead to loss-of-function/absence of pro a2(I) collagen chains cause cardiac-valvular type EDS. 6 cases in 5 unrelated families have been reported with homozygous and compound heterozygous variants (PMID: 30821104).
Sources: Expert list
Aortopathy_Connective Tissue Disorders v0.131 EFEMP2 Zornitza Stark Marked gene: EFEMP2 as ready
Aortopathy_Connective Tissue Disorders v0.131 EFEMP2 Zornitza Stark Gene: efemp2 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.131 EFEMP2 Zornitza Stark Phenotypes for gene: EFEMP2 were changed from to Cutis laxa, autosomal recessive, type IB MIM# 614437
Aortopathy_Connective Tissue Disorders v0.130 FOXE3 Ain Roesley gene: FOXE3 was added
gene: FOXE3 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: FOXE3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXE3 were set to 30071989; 26854927
Review for gene: FOXE3 was set to AMBER
Added comment: PMID: 30071989; classification from “moderate” to “limited” after expert review, because the data provided are limited to single supporting publications with few HTAAD families.

Gene validity curation by ClinGen in 2016 was "moderate", citing segregation in the large family and animal models (https://search.clinicalgenome.org/kb/gene-validity/8261, PMID: 26854927)
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.130 EFEMP2 Zornitza Stark Classified gene: EFEMP2 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.130 EFEMP2 Zornitza Stark Gene: efemp2 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.129 EFEMP2 Paul De Fazio edited their review of gene: EFEMP2: Changed phenotypes: Cutis laxa, autosomal recessive, type IB MIM# 614437
Aortopathy_Connective Tissue Disorders v0.129 EFEMP2 Paul De Fazio gene: EFEMP2 was added
gene: EFEMP2 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: EFEMP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EFEMP2 were set to 20389311; 19664000; 16685658; 17937443; 22943132; 22440127
Review for gene: EFEMP2 was set to GREEN
gene: EFEMP2 was marked as current diagnostic
Added comment: Associated with cutis laxa in at least 6 unrelated individuals (PMID: 20389311; 19664000; 16685658; 17937443).

PMID: 22943132 reports 22 homozygous or compound het infants with: cardiovascular features included aneurysmal dilatation, elongation, tortuosity and narrowing of the aorta, pulmonary artery and their branches. The phenotype included a variable combination of cutis laxa (52%), long philtrum-thin vermillion (90%), micrognathia (43%), hypertelorism (57%), prominent eyes (43%), sagging cheeks (43%), long slender digits (48%), and visible arterial pulsations (38%).

Has also been associated with aortic dissection without presentation of cutis laxa (PMID: 22440127 - reports 9 affected individuals).
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.129 FBLN5 Zornitza Stark Marked gene: FBLN5 as ready
Aortopathy_Connective Tissue Disorders v0.129 FBLN5 Zornitza Stark Gene: fbln5 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.129 FBLN5 Zornitza Stark Classified gene: FBLN5 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.129 FBLN5 Zornitza Stark Gene: fbln5 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.128 FBLN5 Zornitza Stark gene: FBLN5 was added
gene: FBLN5 was added to Aortopathy_Connective Tissue Disorders. Sources: Expert list
Mode of inheritance for gene: FBLN5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FBLN5 were set to 3232707; 22829427; 11805835
Phenotypes for gene: FBLN5 were set to Cutis laxa, autosomal recessive, type IA, MIM# 219100
Review for gene: FBLN5 was set to GREEN
Added comment: >3 families reported and functional data including mouse model.
Sources: Expert list
Aortopathy_Connective Tissue Disorders v0.126 DSE Bryony Thompson Marked gene: DSE as ready
Aortopathy_Connective Tissue Disorders v0.126 DSE Bryony Thompson Gene: dse has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.126 DSE Bryony Thompson Classified gene: DSE as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.126 DSE Bryony Thompson Gene: dse has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.125 DSE Bryony Thompson gene: DSE was added
gene: DSE was added to Aortopathy_Connective Tissue Disorders. Sources: Expert list
Mode of inheritance for gene: DSE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DSE were set to 28306229; 23704329; 25703627; 32130795
Phenotypes for gene: DSE were set to Ehlers-Danlos syndrome, musculocontractural type 2 MIM#615539
Review for gene: DSE was set to GREEN
Added comment: One of the 19 EDS genes recognised by the International EDS Consortium (PMID: 28306229).
8 cases from 6 unrelated families have been reported with homozygous variants.
Sources: Expert list
Aortopathy_Connective Tissue Disorders v0.124 MFAP5 Zornitza Stark Marked gene: MFAP5 as ready
Aortopathy_Connective Tissue Disorders v0.124 MFAP5 Zornitza Stark Gene: mfap5 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.124 MFAP5 Zornitza Stark Classified gene: MFAP5 as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v0.124 MFAP5 Zornitza Stark Gene: mfap5 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.123 ELN Zornitza Stark Marked gene: ELN as ready
Aortopathy_Connective Tissue Disorders v0.123 ELN Zornitza Stark Gene: eln has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.123 MFAP5 Paul De Fazio gene: MFAP5 was added
gene: MFAP5 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: MFAP5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MFAP5 were set to 25434006; 30763214
Phenotypes for gene: MFAP5 were set to Aortic aneurysm, familial thoracic MIM# 616166
Review for gene: MFAP5 was set to AMBER
gene: MFAP5 was marked as current diagnostic
Added comment: 2 families described with thoracic aortic aneurysms and dissections, one with a nonsense variant and one with a missense (PMID:2544006). A recent review doesn't mention any other cases (PMID:30763214).
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.123 CHST14 Zornitza Stark Marked gene: CHST14 as ready
Aortopathy_Connective Tissue Disorders v0.123 CHST14 Zornitza Stark Gene: chst14 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.123 ELN Zornitza Stark Classified gene: ELN as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.123 ELN Zornitza Stark Gene: eln has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.122 FKBP14 Bryony Thompson Classified gene: FKBP14 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.122 FKBP14 Bryony Thompson Gene: fkbp14 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.122 CHST14 Zornitza Stark Classified gene: CHST14 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.122 CHST14 Zornitza Stark Gene: chst14 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.121 FKBP14 Bryony Thompson Classified gene: FKBP14 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.121 FKBP14 Bryony Thompson Gene: fkbp14 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.121 FKBP14 Bryony Thompson Marked gene: FKBP14 as ready
Aortopathy_Connective Tissue Disorders v0.121 FKBP14 Bryony Thompson Gene: fkbp14 has been classified as Red List (Low Evidence).
Aortopathy_Connective Tissue Disorders v0.121 CHST14 Zornitza Stark Classified gene: CHST14 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.121 CHST14 Zornitza Stark Gene: chst14 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.120 FKBP14 Bryony Thompson changed review comment from: One of the 19 EDS genes recognised by the International EDS Consortium (PMID: 28306229).
At least 6 unrelated families with homozygous or compound heterozygous variants reported.
Sources: Expert list; to: One of the 19 EDS genes recognised by the International EDS Consortium (PMID: 28306229).
At least 6 unrelated families with homozygous or compound heterozygous variants reported with this EDS subtype.
Sources: Expert list
Aortopathy_Connective Tissue Disorders v0.120 FKBP14 Bryony Thompson edited their review of gene: FKBP14: Changed rating: GREEN
Aortopathy_Connective Tissue Disorders v0.120 FKBP14 Bryony Thompson gene: FKBP14 was added
gene: FKBP14 was added to Aortopathy_Connective Tissue Disorders. Sources: Expert list
Mode of inheritance for gene: FKBP14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FKBP14 were set to 22265013; 28306229; 24773188; 27149304
Phenotypes for gene: FKBP14 were set to Ehlers-Danlos syndrome, kyphoscoliotic type, 2 MIM#614557
Added comment: One of the 19 EDS genes recognised by the International EDS Consortium (PMID: 28306229).
At least 6 unrelated families with homozygous or compound heterozygous variants reported.
Sources: Expert list
Aortopathy_Connective Tissue Disorders v0.119 ATP6V0A2 Zornitza Stark Marked gene: ATP6V0A2 as ready
Aortopathy_Connective Tissue Disorders v0.119 ATP6V0A2 Zornitza Stark Gene: atp6v0a2 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.119 ATP6V0A2 Zornitza Stark Classified gene: ATP6V0A2 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.119 ATP6V0A2 Zornitza Stark Gene: atp6v0a2 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.118 NOTCH1 Zornitza Stark Marked gene: NOTCH1 as ready
Aortopathy_Connective Tissue Disorders v0.118 NOTCH1 Zornitza Stark Gene: notch1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.118 NOTCH1 Zornitza Stark Phenotypes for gene: NOTCH1 were changed from Aortic valve disease MIM# 109730 to Aortic valve disease MIM# 109730; Thoracic aortic aneurysm
Aortopathy_Connective Tissue Disorders v0.117 NOTCH1 Zornitza Stark Classified gene: NOTCH1 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.117 NOTCH1 Zornitza Stark Gene: notch1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.116 ALDH18A1 Zornitza Stark Marked gene: ALDH18A1 as ready
Aortopathy_Connective Tissue Disorders v0.116 ALDH18A1 Zornitza Stark Gene: aldh18a1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.116 ALDH18A1 Zornitza Stark Classified gene: ALDH18A1 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.116 ALDH18A1 Zornitza Stark Gene: aldh18a1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.115 SMAD6 Zornitza Stark Marked gene: SMAD6 as ready
Aortopathy_Connective Tissue Disorders v0.115 SMAD6 Zornitza Stark Added comment: Comment when marking as ready: Primarily associated with aortic valve disease, but increased prevalence of thoracic aneurysm also documented.
Aortopathy_Connective Tissue Disorders v0.115 SMAD6 Zornitza Stark Gene: smad6 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.115 SMAD6 Zornitza Stark Classified gene: SMAD6 as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v0.115 SMAD6 Zornitza Stark Gene: smad6 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.114 PLOD1 Bryony Thompson Marked gene: PLOD1 as ready
Aortopathy_Connective Tissue Disorders v0.114 PLOD1 Bryony Thompson Gene: plod1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.114 PLOD1 Bryony Thompson Classified gene: PLOD1 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.114 PLOD1 Bryony Thompson Gene: plod1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.113 PRDM5 Bryony Thompson Marked gene: PRDM5 as ready
Aortopathy_Connective Tissue Disorders v0.113 PRDM5 Bryony Thompson Gene: prdm5 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.113 PRDM5 Bryony Thompson Classified gene: PRDM5 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.113 PRDM5 Bryony Thompson Gene: prdm5 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.112 PRDM5 Bryony Thompson gene: PRDM5 was added
gene: PRDM5 was added to Aortopathy_Connective Tissue Disorders. Sources: Expert list
Mode of inheritance for gene: PRDM5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRDM5 were set to 28306229; 21664999
Phenotypes for gene: PRDM5 were set to Brittle cornea syndrome 2, MIM#614170
Review for gene: PRDM5 was set to GREEN
Added comment: One of the 19 EDS genes recognised by the International EDS Consortium (PMID: 28306229). Homozygous variants identified in at least 7 unrelated confirmed/likely consanguineous brittle cornea syndrome families. The mutation spectrum included stopgain, missense, splice site, and a large deletion.
Sources: Expert list
Aortopathy_Connective Tissue Disorders v0.111 ABCC6 Zornitza Stark Marked gene: ABCC6 as ready
Aortopathy_Connective Tissue Disorders v0.111 ABCC6 Zornitza Stark Gene: abcc6 has been classified as Red List (Low Evidence).
Aortopathy_Connective Tissue Disorders v0.111 ABCC6 Zornitza Stark Classified gene: ABCC6 as Red List (low evidence)
Aortopathy_Connective Tissue Disorders v0.111 ABCC6 Zornitza Stark Gene: abcc6 has been classified as Red List (Low Evidence).
Aortopathy_Connective Tissue Disorders v0.111 SLC39A13 Bryony Thompson Marked gene: SLC39A13 as ready
Aortopathy_Connective Tissue Disorders v0.111 SLC39A13 Bryony Thompson Gene: slc39a13 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.111 SLC39A13 Bryony Thompson Classified gene: SLC39A13 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.111 SLC39A13 Bryony Thompson Gene: slc39a13 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.110 ABCC6 Zornitza Stark reviewed gene: ABCC6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Aortopathy_Connective Tissue Disorders v0.110 TNXB Bryony Thompson Marked gene: TNXB as ready
Aortopathy_Connective Tissue Disorders v0.110 TNXB Bryony Thompson Gene: tnxb has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.110 TNXB Bryony Thompson Classified gene: TNXB as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.110 TNXB Bryony Thompson Added comment: Comment on list classification: One of the 19 EDS genes recognised by the International EDS Consortium (PMID: 28306229)
Aortopathy_Connective Tissue Disorders v0.110 TNXB Bryony Thompson Gene: tnxb has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.109 ZNF469 Bryony Thompson Marked gene: ZNF469 as ready
Aortopathy_Connective Tissue Disorders v0.109 ZNF469 Bryony Thompson Gene: znf469 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.109 ZNF469 Bryony Thompson Classified gene: ZNF469 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.109 ZNF469 Bryony Thompson Added comment: Comment on list classification: One of the 19 EDS genes recognised by the International EDS Consortium (PMID: 28306229)
Aortopathy_Connective Tissue Disorders v0.109 ZNF469 Bryony Thompson Gene: znf469 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.108 C1S Bryony Thompson Publications for gene: C1S were set to 30071989; 27745832; 31921203
Aortopathy_Connective Tissue Disorders v0.107 C1S Bryony Thompson Classified gene: C1S as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v0.107 C1S Bryony Thompson Added comment: Comment on list classification: One of the 19 EDS genes recognised by the International EDS Consortium (PMID: 28306229)
Aortopathy_Connective Tissue Disorders v0.107 C1S Bryony Thompson Gene: c1s has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.106 ELN Belinda Chong gene: ELN was added
gene: ELN was added to Aortopathy_Connective Tissue Disorders. Sources: Other
Mode of inheritance for gene: ELN was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ELN were set to 27866049; 31560829; 19844261; 19844261
Phenotypes for gene: ELN were set to Cutis laxa 123700; Supravalvar aortic stenosis 185500
Review for gene: ELN was set to GREEN
Added comment: >3 families with Cutis laxa or Supravalvar aortic stenosis.

PMID: 30071989
Assertion made by the Aortopathy working group. So far there is no evidence that patients with ELN mutations present with aortic dissection or progressive aortic enlargement. Functional evidence, however, supports a role for ELN in HTAAD. ELN mutations cause AD cutis laxa syndrome, a disease with low risk for thoracic aortic disease and primarily diagnosed based on non-vascular features
Sources: Other
Aortopathy_Connective Tissue Disorders v0.106 CHST14 Ain Roesley gene: CHST14 was added
gene: CHST14 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: CHST14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHST14 were set to PMID: 28306229; 25703627; 26373698
Phenotypes for gene: CHST14 were set to Ehlers-Danlos syndrome, musculocontractural type 1 (MIM# 601776)
Review for gene: CHST14 was set to GREEN
Added comment: PMID: 28306229; one of the EDS genes recognised by the International EDS Consortium

PMID: 25703627, 5 individuals from 4 families
PMID: 26373698, 7 individuals from 4 families
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.106 C1R Bryony Thompson Marked gene: C1R as ready
Aortopathy_Connective Tissue Disorders v0.106 C1R Bryony Thompson Gene: c1r has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.106 C1R Bryony Thompson Phenotypes for gene: C1R were changed from to Ehlers-Danlos syndrome, periodontal type, 1 (MIM# 130080)
Aortopathy_Connective Tissue Disorders v0.105 C1R Bryony Thompson Publications for gene: C1R were set to
Aortopathy_Connective Tissue Disorders v0.104 C1R Bryony Thompson Mode of inheritance for gene: C1R was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.104 C1R Bryony Thompson Mode of inheritance for gene: C1R was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.103 C1R Bryony Thompson Classified gene: C1R as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.103 C1R Bryony Thompson Added comment: Comment on list classification: One of the 19 EDS genes recognised by the International EDS Consortium (PMID: 28306229)
Aortopathy_Connective Tissue Disorders v0.103 C1R Bryony Thompson Gene: c1r has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.102 B4GALT7 Bryony Thompson Marked gene: B4GALT7 as ready
Aortopathy_Connective Tissue Disorders v0.102 B4GALT7 Bryony Thompson Gene: b4galt7 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.102 B4GALT7 Bryony Thompson Classified gene: B4GALT7 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.102 B4GALT7 Bryony Thompson Gene: b4galt7 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.101 B4GALT7 Bryony Thompson gene: B4GALT7 was added
gene: B4GALT7 was added to Aortopathy_Connective Tissue Disorders. Sources: Expert list
Mode of inheritance for gene: B4GALT7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: B4GALT7 were set to 28306229; 26940150; 24755949; 23956117
Phenotypes for gene: B4GALT7 were set to Ehlers-Danlos syndrome with short stature and limb anomalies, 130070; Spondylodysplastic EDS
Review for gene: B4GALT7 was set to GREEN
Added comment: One of the 19 EDS genes recognised by the International EDS Consortium (PMID: 28306229).
At least 6 families reported with compound heterozygous or homozygous variants, with a spondylodysplastic EDS phenotype.
Sources: Expert list
Aortopathy_Connective Tissue Disorders v0.100 ATP6V0A2 Ain Roesley gene: ATP6V0A2 was added
gene: ATP6V0A2 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: ATP6V0A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP6V0A2 were set to PMID: 23963297
Phenotypes for gene: ATP6V0A2 were set to Cutis laxa, autosomal recessive, type IIA (MIM# 219200), Wrinkly skin syndrome (MIM# 278250)
Penetrance for gene: ATP6V0A2 were set to unknown
Review for gene: ATP6V0A2 was set to GREEN
Added comment: PMID: 23963297; 6 patients from 5 unrelated families with cutis laxa

PMID: 30071989; not a gene for HTAAD by clingen working group
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.100 B3GALT6 Bryony Thompson Marked gene: B3GALT6 as ready
Aortopathy_Connective Tissue Disorders v0.100 B3GALT6 Bryony Thompson Gene: b3galt6 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.100 B3GALT6 Bryony Thompson Classified gene: B3GALT6 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.100 B3GALT6 Bryony Thompson Gene: b3galt6 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.99 B3GALT6 Bryony Thompson gene: B3GALT6 was added
gene: B3GALT6 was added to Aortopathy_Connective Tissue Disorders. Sources: Expert list
Mode of inheritance for gene: B3GALT6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: B3GALT6 were set to 29931299; 28306229
Phenotypes for gene: B3GALT6 were set to Ehlers Danlos syndrome, progeroid type, 2, 615349; Spondylodysplastic EDS
Review for gene: B3GALT6 was set to GREEN
Added comment: One of the 19 EDS genes recognised by the International EDS Consortium (PMID: 28306229).
In 12 patients from 9 families with EDSSPD2, 8 compound heterozygous mutations and 1 homozygous mutation in B3GALT6 were identified, including 11 missense variants, 2 frameshift variants, a deletion of 19 amino acids, and a start codon alteration (PMID: 29931299).
Sources: Expert list
Aortopathy_Connective Tissue Disorders v0.98 ADAMTS2 Bryony Thompson Marked gene: ADAMTS2 as ready
Aortopathy_Connective Tissue Disorders v0.98 ADAMTS2 Bryony Thompson Gene: adamts2 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.98 ADAMTS2 Bryony Thompson Publications for gene: ADAMTS2 were set to PMID: 30071989; 26765342
Aortopathy_Connective Tissue Disorders v0.97 ADAMTS2 Bryony Thompson Classified gene: ADAMTS2 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.97 ADAMTS2 Bryony Thompson Added comment: Comment on list classification: One of the 19 EDS genes recognised by the International EDS Consortium (PMID: 28306229)
Aortopathy_Connective Tissue Disorders v0.97 ADAMTS2 Bryony Thompson Gene: adamts2 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.96 NOTCH1 Paul De Fazio gene: NOTCH1 was added
gene: NOTCH1 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: NOTCH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NOTCH1 were set to 16729972; 26820064; 16025100; 25963545
Phenotypes for gene: NOTCH1 were set to Aortic valve disease MIM# 109730
Review for gene: NOTCH1 was set to GREEN
Added comment: NOTCH1 variants are associated with cardiac abnormalities including aortic valve stenosis, a bicuspid aortic valve, coarctation of the aorta, hypoplastic left heart syndrome, and thoracic aortic aneurysms in nonsyndromic individuals (2 families in PMID:16025100; 2 individuals in PMID:16729972; 14 families in PMID:26820064). Penetrance is incomplete and not all individuals display all phenotypes (e.g. only 6/63 individuals from PMID:26820064 had thoracic aortic aneurysms).

Monoallelic NOTCH1 variants are also responsible for Adams-Oliver syndrome, which can have associated cardiac abnormalities (PMID: 25963545).
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.96 TNXB Paul De Fazio gene: TNXB was added
gene: TNXB was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: TNXB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TNXB were set to 28306229; 28306225; 23620400
Phenotypes for gene: TNXB were set to Ehlers-Danlos syndrome, classic-like, 1 MIM# 606408
Review for gene: TNXB was set to GREEN
gene: TNXB was marked as current diagnostic
Added comment: Association with classic Ehlers-Danlos syndrome is well-established (PMID:28306229;28306225).

Two families have also been described with Vesicoureteral Reflux caused by a heterozygous missense variant in this gene, some individuals were reported with asymptomatic joint hypermobility (PMID:23620400)
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.96 PLOD1 Paul De Fazio gene: PLOD1 was added
gene: PLOD1 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: PLOD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLOD1 were set to 28306225; 28306229
Phenotypes for gene: PLOD1 were set to Ehlers-Danlos syndrome, kyphoscoliotic type, MIM# 225400
Review for gene: PLOD1 was set to GREEN
gene: PLOD1 was marked as current diagnostic
Added comment: Review in PMID: 28306225 states: "A total of 139 mutations in PLOD1 have been identified in the 84 confirmed cases, of these there are 39 different mutations." It is included in The 2017 International Classification of the Ehlers-Danlos Syndromes (PMID: 28306229).

Medium‐sized vessel rupture has been reported in several individual case reports.
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.96 SLC39A13 Paul De Fazio gene: SLC39A13 was added
gene: SLC39A13 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: SLC39A13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC39A13 were set to 18985159; 18513683; 28306229; 28306225
Phenotypes for gene: SLC39A13 were set to Ehlers-Danlos syndrome, spondylodysplastic type, MIM# 612350
Review for gene: SLC39A13 was set to GREEN
gene: SLC39A13 was marked as current diagnostic
Added comment: 3 unrelated families described to date (PMID: 18985159;18513683). Is included in The 2017 International Classification of the Ehlers-Danlos Syndromes (PMID: 28306229). See PMID: 28306225 for a review.
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.96 ALDH18A1 Ain Roesley gene: ALDH18A1 was added
gene: ALDH18A1 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: ALDH18A1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: ALDH18A1 were set to PMID: 30071989; 26320891; 24913064; 18478038; 21739576; 22411858; 28228640
Phenotypes for gene: ALDH18A1 were set to Cutis laxa, autosomal dominant 3 (MIM# 616603); Cutis laxa, autosomal recessive, type IIIA (MIM# 219150)
Review for gene: ALDH18A1 was set to GREEN
Added comment: PMID: 30071989; not a HTAAD gene by clingen working group

Cutis laxa, autosomal dominant 3 (MIM# 616603)

PMID: 28228640;
- Born to consanguineous parents and harbour a de novo missense p.(Arg126His). no functional done

PMID: 26320891;
- 8 unrelated individuals born to non-consanguineous families clinically diagnosed with de-barsy syndrome (DBS) or wrinkly skin syndrome. All variants occur at codon Arg138 and parental DNA from 6 probands confirmed de novo origin. (NOTE: table 1 states paternal origin however this is referring to the allele not variant (Figure S1)).
- Imaging of patients's cells showed increased accumulation of mutant protein at the mitochondrial outer membrane.
- Biochemical studies using patients' fibroblasts demonstrated LoF


Cutis laxa, autosomal recessive, type IIIA (MIM# 219150)

PMID: 24913064;
- 2 patients from consanguineous families, 1x fs (c.2131del)+ 1x 1522bp del (resulting in exon 15 del)
- clinical features like facial dysmorphism, hypotonia, adducted thumbs and cutis laxa, which are frequently found in progeroid cutis laxa syndromes. In addition, they had cardiovascular abnormalities

PMID: 18478038;
- missense c.2350C>T; p.(His784Tyr) found in a a consanguineous New Zealand Maori family with 4 affecteds.
- patients' fibroblasts showed no defect in Proline accumulation

PMID: 21739576;
This severely affected child, born to consanguineous parents of Pakistani origin, presented with lax, wrinkled and thin skin with dilated and tortuous subcutaneous blood vessels, corneal clouding, and hypotonia. The child had severe global developmental delay and feeding difficulties and died in infancy for an unknown reason. The proband was homozygous for a mutation in ALDH18A1 , c.1923 + 1G > A

PMID: 22411858;
pair of siblings chet for p.(Ser742Ile) and p.(Arg425Cys)
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.96 SMAD6 Paul De Fazio gene: SMAD6 was added
gene: SMAD6 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: SMAD6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SMAD6 were set to 22275001; 28659821; 30963242; 30848080; 30796334
Phenotypes for gene: SMAD6 were set to Aortic valve disease 2 MIM# 614823
Review for gene: SMAD6 was set to AMBER
gene: SMAD6 was marked as current diagnostic
Added comment: Missense and LOF SMAD6 variants described as pathogenic or likely pathogenic have been identified in at least 20 individuals from bicuspid aortic valve/nonsyndromic thoracic aortic aneurysm cohorts (PMID:22275001, 30848080, 28659821, 30796334).

Functional studies on two of the missense variants supported abnormal function, but a third variant did not show any functional defect (and was also not well-conserved) (PMID:22275001).

Familial segregation studies in PMID: 30796334 demonstrated reduced penetrance (82%) and variable clinical expressivity, with coarctation of the aorta being a common comorbidity.

Biallelic variants have been decribed in 2 individuals with 'complex cardiac phenotype' (including aortic isthmus stenosis, dysplastic and stenotic pulmonary valve, and dilated cardiomyopathy) (PMID: 30963242).

There appears to be a clear gene-disease relationship but I am not sure if it belongs in this panel.
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.96 ADAMTS2 Ain Roesley gene: ADAMTS2 was added
gene: ADAMTS2 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: ADAMTS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAMTS2 were set to PMID: 30071989; 26765342
Phenotypes for gene: ADAMTS2 were set to Ehlers-Danlos syndrome, dermatosparaxis type (MIM# 225410)
Review for gene: ADAMTS2 was set to GREEN
Added comment: PMID: 30071989; not a gene for HTAAD by Clingen working group

PMID: 26765342;
5 patients form 4 unrelated families (3 PTVs + 1 exon del). qPCR of total RNA demonstrated significantly reduced ADAMTS2 expression and LoF was further supported by functional assays using dermal fibroblasts.
Authors noted that Family 1 and Patient 5 are clinically milder and hypothesised that their C-term variants may lead to some transcripts escaping NMD, producing a truncated yet partially functional protein.
Figure 2 provides an additional 6 previously reported variants (2 PTVs + 4 exon dels.
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.96 ACVR1 Ain Roesley gene: ACVR1 was added
gene: ACVR1 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: ACVR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ACVR1 were set to PMID: 30071989; 19085907; 26776312; 18684712; 23572558; 20463014
Phenotypes for gene: ACVR1 were set to Fibrodysplasia ossificans progressiva (MIM# 135100)
Review for gene: ACVR1 was set to AMBER
Added comment: Fibrodysplasia ossificans progressiva is a rare autosomal dominant disease with complete penetrance involving progressive ossification of skeletal muscle, fascia, tendons, and ligaments.

PMID: 19085907; 112 FOP (classic and atypical) cases (104 sporadic and 8 families) with R206H has the recurrent variant and a greater clinical variability seen in non-R206H patients (PMID: 26776312)

PMID: 18684712, 23572558, 20463014; functional studies demonstrating GoF

PMID: 30071989; not a HTAAD gene by Clingen working group
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.96 ZNF469 Paul De Fazio edited their review of gene: ZNF469: Changed phenotypes: Brittle cornea syndrome 1 MIM# 229200
Aortopathy_Connective Tissue Disorders v0.96 ZNF469 Paul De Fazio gene: ZNF469 was added
gene: ZNF469 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: ZNF469 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF469 were set to 28306229; 28306225
Phenotypes for gene: ZNF469 were set to Brittle cornea syndrome 1
Review for gene: ZNF469 was set to GREEN
gene: ZNF469 was marked as current diagnostic
Added comment: Association with brittle cornea syndrome (BCS) is well-established. 32 patients with variants in ZNF469 and BCS are reviewed in PMID: 28306225.

BCS is classified as a form of Ehlers-Danlos syndrome (PMID: 28306229).
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.96 ABCC6 Ain Roesley gene: ABCC6 was added
gene: ABCC6 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: ABCC6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABCC6 were set to PMID: 30071989; 11536079
Phenotypes for gene: ABCC6 were set to Pseudoxanthoma elasticum (MIM# 264800)
Review for gene: ABCC6 was set to AMBER
Added comment: PMID: 30071989; not a gene for Heritable Thoracic Aortic Aneurysm and Dissection by Clingen Working Group

PMID: 11536079; a cohort of 122 PXE patients were sequenced and 36 different variants were reported
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.96 COL5A2 Zornitza Stark Marked gene: COL5A2 as ready
Aortopathy_Connective Tissue Disorders v0.96 COL5A2 Zornitza Stark Gene: col5a2 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.96 COL5A2 Zornitza Stark Mode of inheritance for gene: COL5A2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.95 COL5A2 Zornitza Stark Classified gene: COL5A2 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.95 COL5A2 Zornitza Stark Gene: col5a2 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.94 C1S Zornitza Stark Marked gene: C1S as ready
Aortopathy_Connective Tissue Disorders v0.94 C1S Zornitza Stark Gene: c1s has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.94 C1S Zornitza Stark Phenotypes for gene: C1S were changed from to Ehlers-Danlos syndrome, periodontal type, 1 (MIM# 130080)
Aortopathy_Connective Tissue Disorders v0.93 C1S Zornitza Stark Publications for gene: C1S were set to
Aortopathy_Connective Tissue Disorders v0.92 C1S Zornitza Stark Mode of inheritance for gene: C1S was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.91 TGFBR2 Zornitza Stark Marked gene: TGFBR2 as ready
Aortopathy_Connective Tissue Disorders v0.91 TGFBR2 Zornitza Stark Gene: tgfbr2 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.91 TGFBR2 Zornitza Stark Phenotypes for gene: TGFBR2 were changed from to Loeys-Dietz syndrome 2, MIM# 610168
Aortopathy_Connective Tissue Disorders v0.90 TGFBR2 Zornitza Stark Publications for gene: TGFBR2 were set to
Aortopathy_Connective Tissue Disorders v0.89 TGFBR2 Zornitza Stark Mode of inheritance for gene: TGFBR2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.88 TGFBR1 Zornitza Stark Marked gene: TGFBR1 as ready
Aortopathy_Connective Tissue Disorders v0.88 TGFBR1 Zornitza Stark Gene: tgfbr1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.88 TGFBR1 Zornitza Stark Phenotypes for gene: TGFBR1 were changed from to Loeys-Dietz syndrome 1, MIM# 609192
Aortopathy_Connective Tissue Disorders v0.87 TGFBR1 Zornitza Stark Publications for gene: TGFBR1 were set to
Aortopathy_Connective Tissue Disorders v0.86 TGFBR1 Zornitza Stark Mode of inheritance for gene: TGFBR1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.85 TGFB3 Zornitza Stark Marked gene: TGFB3 as ready
Aortopathy_Connective Tissue Disorders v0.85 TGFB3 Zornitza Stark Gene: tgfb3 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.85 TGFB3 Zornitza Stark Phenotypes for gene: TGFB3 were changed from to Loeys-Dietz syndrome 5, MI# 615582
Aortopathy_Connective Tissue Disorders v0.84 TGFB3 Zornitza Stark Publications for gene: TGFB3 were set to
Aortopathy_Connective Tissue Disorders v0.83 TGFB3 Zornitza Stark Mode of inheritance for gene: TGFB3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.82 TGFB2 Zornitza Stark Marked gene: TGFB2 as ready
Aortopathy_Connective Tissue Disorders v0.82 TGFB2 Zornitza Stark Gene: tgfb2 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.82 TGFB2 Zornitza Stark Phenotypes for gene: TGFB2 were changed from to Loeys-Dietz syndrome 4, MIM# 614816
Aortopathy_Connective Tissue Disorders v0.81 TGFB2 Zornitza Stark Publications for gene: TGFB2 were set to
Aortopathy_Connective Tissue Disorders v0.80 TGFB2 Zornitza Stark Mode of inheritance for gene: TGFB2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.79 SLC2A10 Zornitza Stark Marked gene: SLC2A10 as ready
Aortopathy_Connective Tissue Disorders v0.79 SLC2A10 Zornitza Stark Gene: slc2a10 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.79 SLC2A10 Zornitza Stark Phenotypes for gene: SLC2A10 were changed from to Arterial tortuosity syndrome MIM#606145
Aortopathy_Connective Tissue Disorders v0.78 SLC2A10 Zornitza Stark Publications for gene: SLC2A10 were set to
Aortopathy_Connective Tissue Disorders v0.77 SLC2A10 Zornitza Stark Mode of inheritance for gene: SLC2A10 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Aortopathy_Connective Tissue Disorders v0.76 SKI Zornitza Stark Marked gene: SKI as ready
Aortopathy_Connective Tissue Disorders v0.76 SKI Zornitza Stark Added comment: Comment when marking as ready: Syndromic connective tissue disorder.
Aortopathy_Connective Tissue Disorders v0.76 SKI Zornitza Stark Gene: ski has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.76 SKI Zornitza Stark Phenotypes for gene: SKI were changed from to Shprintzen-Goldberg syndrome, MIM#164780
Aortopathy_Connective Tissue Disorders v0.75 SKI Zornitza Stark Publications for gene: SKI were set to
Aortopathy_Connective Tissue Disorders v0.74 SKI Zornitza Stark Mode of inheritance for gene: SKI was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.73 PRKG1 Zornitza Stark Marked gene: PRKG1 as ready
Aortopathy_Connective Tissue Disorders v0.73 PRKG1 Zornitza Stark Gene: prkg1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.73 PRKG1 Zornitza Stark Phenotypes for gene: PRKG1 were changed from to Aortic aneurysm, familial thoracic 8, MIM#176894
Aortopathy_Connective Tissue Disorders v0.72 PRKG1 Zornitza Stark Publications for gene: PRKG1 were set to
Aortopathy_Connective Tissue Disorders v0.71 PRKG1 Zornitza Stark Mode of inheritance for gene: PRKG1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.70 PCGF2 Zornitza Stark Marked gene: PCGF2 as ready
Aortopathy_Connective Tissue Disorders v0.70 PCGF2 Zornitza Stark Gene: pcgf2 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.70 PCGF2 Zornitza Stark Phenotypes for gene: PCGF2 were changed from to Turnpenny-Fry syndrome, MIM#600346
Aortopathy_Connective Tissue Disorders v0.69 PCGF2 Zornitza Stark Publications for gene: PCGF2 were set to
Aortopathy_Connective Tissue Disorders v0.68 PCGF2 Zornitza Stark Mode of inheritance for gene: PCGF2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.67 MYLK Zornitza Stark Marked gene: MYLK as ready
Aortopathy_Connective Tissue Disorders v0.67 MYLK Zornitza Stark Gene: mylk has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.67 MYLK Zornitza Stark Phenotypes for gene: MYLK were changed from to Aortic aneurysm, familial thoracic 7, MIM#600922
Aortopathy_Connective Tissue Disorders v0.66 MYLK Zornitza Stark Publications for gene: MYLK were set to
Aortopathy_Connective Tissue Disorders v0.65 MYLK Zornitza Stark Mode of inheritance for gene: MYLK was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.64 MYH11 Zornitza Stark Marked gene: MYH11 as ready
Aortopathy_Connective Tissue Disorders v0.64 MYH11 Zornitza Stark Gene: myh11 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.64 MYH11 Zornitza Stark Phenotypes for gene: MYH11 were changed from to Aortic aneurysm, familial thoracic 4, MIM#160745
Aortopathy_Connective Tissue Disorders v0.63 MYH11 Zornitza Stark Publications for gene: MYH11 were set to
Aortopathy_Connective Tissue Disorders v0.62 MED12 Zornitza Stark Marked gene: MED12 as ready
Aortopathy_Connective Tissue Disorders v0.62 MED12 Zornitza Stark Gene: med12 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.62 MED12 Zornitza Stark Phenotypes for gene: MED12 were changed from to Lujan-Fryns syndrome, MIM# 309520; Ohdo syndrome, X-linked, MIM# 300895; Opitz-Kaveggia syndrome, MIM# 305450
Aortopathy_Connective Tissue Disorders v0.61 MED12 Zornitza Stark Publications for gene: MED12 were set to
Aortopathy_Connective Tissue Disorders v0.60 MED12 Zornitza Stark Mode of inheritance for gene: MED12 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Aortopathy_Connective Tissue Disorders v0.59 LOX Zornitza Stark Marked gene: LOX as ready
Aortopathy_Connective Tissue Disorders v0.59 LOX Zornitza Stark Gene: lox has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.59 LOX Zornitza Stark Phenotypes for gene: LOX were changed from to Aortic aneurysm, familial thoracic 10, MIM#617168
Aortopathy_Connective Tissue Disorders v0.58 LOX Zornitza Stark Publications for gene: LOX were set to
Aortopathy_Connective Tissue Disorders v0.57 LOX Zornitza Stark Mode of inheritance for gene: LOX was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.56 FBN1 Zornitza Stark Marked gene: FBN1 as ready
Aortopathy_Connective Tissue Disorders v0.56 FBN1 Zornitza Stark Gene: fbn1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.56 FBN1 Zornitza Stark Phenotypes for gene: FBN1 were changed from to Marfan syndrome (154700); MASS syndrome (604308)
Aortopathy_Connective Tissue Disorders v0.55 FBN1 Zornitza Stark Publications for gene: FBN1 were set to
Aortopathy_Connective Tissue Disorders v0.54 FBN1 Zornitza Stark Mode of inheritance for gene: FBN1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.53 COL5A1 Zornitza Stark Marked gene: COL5A1 as ready
Aortopathy_Connective Tissue Disorders v0.53 COL5A1 Zornitza Stark Gene: col5a1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.53 COL5A1 Zornitza Stark Phenotypes for gene: COL5A1 were changed from to Ehlers-Danlos syndrome, classic type, 1, MIM# 130000
Aortopathy_Connective Tissue Disorders v0.52 COL5A1 Zornitza Stark Publications for gene: COL5A1 were set to
Aortopathy_Connective Tissue Disorders v0.51 COL5A1 Zornitza Stark Mode of inheritance for gene: COL5A1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.50 COL3A1 Zornitza Stark Marked gene: COL3A1 as ready
Aortopathy_Connective Tissue Disorders v0.50 COL3A1 Zornitza Stark Gene: col3a1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.50 COL3A1 Zornitza Stark Phenotypes for gene: COL3A1 were changed from to Ehlers-Danlos syndrome, vascular type, MIM# 130050; Polymicrogyria with or without vascular-type EDS, MIM# 618343
Aortopathy_Connective Tissue Disorders v0.49 COL3A1 Zornitza Stark Mode of inheritance for gene: COL3A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Aortopathy_Connective Tissue Disorders v0.48 COL3A1 Zornitza Stark Publications for gene: COL3A1 were set to
Aortopathy_Connective Tissue Disorders v0.47 COL3A1 Zornitza Stark Mode of inheritance for gene: COL3A1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.46 COL1A1 Zornitza Stark Marked gene: COL1A1 as ready
Aortopathy_Connective Tissue Disorders v0.46 COL1A1 Zornitza Stark Gene: col1a1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.46 COL1A1 Zornitza Stark Phenotypes for gene: COL1A1 were changed from to Ehlers-Danlos syndrome, arthrochalasia type, 1, MIM# 130060
Aortopathy_Connective Tissue Disorders v0.45 COL1A1 Zornitza Stark Publications for gene: COL1A1 were set to
Aortopathy_Connective Tissue Disorders v0.44 COL1A1 Zornitza Stark Mode of inheritance for gene: COL1A1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.43 CBS Zornitza Stark Marked gene: CBS as ready
Aortopathy_Connective Tissue Disorders v0.43 CBS Zornitza Stark Gene: cbs has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.43 CBS Zornitza Stark Phenotypes for gene: CBS were changed from to Homocystinuria (MIM# 236200)
Aortopathy_Connective Tissue Disorders v0.42 CBS Zornitza Stark Publications for gene: CBS were set to
Aortopathy_Connective Tissue Disorders v0.41 CBS Zornitza Stark Mode of inheritance for gene: CBS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Aortopathy_Connective Tissue Disorders v0.40 CBS Zornitza Stark reviewed gene: CBS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Aortopathy_Connective Tissue Disorders v0.40 BGN Zornitza Stark Marked gene: BGN as ready
Aortopathy_Connective Tissue Disorders v0.40 BGN Zornitza Stark Added comment: Comment when marking as ready: Females variably affected.
Aortopathy_Connective Tissue Disorders v0.40 BGN Zornitza Stark Gene: bgn has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.40 BGN Zornitza Stark Marked gene: BGN as ready
Aortopathy_Connective Tissue Disorders v0.40 BGN Zornitza Stark Gene: bgn has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.40 BGN Zornitza Stark Mode of inheritance for gene: BGN 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)
Aortopathy_Connective Tissue Disorders v0.39 BGN Zornitza Stark Publications for gene: BGN were set to
Aortopathy_Connective Tissue Disorders v0.38 BGN Zornitza Stark Phenotypes for gene: BGN were changed from to Meester-Loeys syndrome, MIM# 300989
Aortopathy_Connective Tissue Disorders v0.37 ACTA2 Zornitza Stark Marked gene: ACTA2 as ready
Aortopathy_Connective Tissue Disorders v0.37 ACTA2 Zornitza Stark Gene: acta2 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.37 ACTA2 Zornitza Stark Phenotypes for gene: ACTA2 were changed from to Aortic aneurysm, familial thoracic 6, MIM# 611788
Aortopathy_Connective Tissue Disorders v0.36 ACTA2 Zornitza Stark Publications for gene: ACTA2 were set to
Aortopathy_Connective Tissue Disorders v0.35 ACTA2 Zornitza Stark Mode of inheritance for gene: ACTA2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.34 ABL1 Zornitza Stark Marked gene: ABL1 as ready
Aortopathy_Connective Tissue Disorders v0.34 ABL1 Zornitza Stark Gene: abl1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.34 ABL1 Zornitza Stark Phenotypes for gene: ABL1 were changed from to Congenital heart defects and skeletal malformations syndrome (MIM# 617602)
Aortopathy_Connective Tissue Disorders v0.33 ABL1 Zornitza Stark Publications for gene: ABL1 were set to
Aortopathy_Connective Tissue Disorders v0.32 ABL1 Zornitza Stark Mode of inheritance for gene: ABL1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.30 COL5A2 Paul De Fazio changed review comment from: Well-known association with classic Ehlers-Danlos syndrome e.g. PMID 22696272. Reviewed in PMID 20847697 and GeneReviews (Available from: https://www.ncbi.nlm.nih.gov/books/NBK1244/).
Sources: Literature; to: Well-known association with classic Ehlers-Danlos syndrome e.g. PMID 22696272. Variants in this gene make up ~14% of cases. Reviewed in PMID 20847697 and GeneReviews (Available from: https://www.ncbi.nlm.nih.gov/books/NBK1244/).
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.30 COL5A2 Paul De Fazio gene: COL5A2 was added
gene: COL5A2 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: COL5A2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: COL5A2 were set to 20847697; 22696272
Phenotypes for gene: COL5A2 were set to Ehlers-Danlos syndrome, classic type, 2, MIM#120190
Penetrance for gene: COL5A2 were set to unknown
Review for gene: COL5A2 was set to GREEN
gene: COL5A2 was marked as current diagnostic
Added comment: Well-known association with classic Ehlers-Danlos syndrome e.g. PMID 22696272. Reviewed in PMID 20847697 and GeneReviews (Available from: https://www.ncbi.nlm.nih.gov/books/NBK1244/).
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.30 MED12 Ain Roesley edited their review of gene: MED12: Changed rating: GREEN
Aortopathy_Connective Tissue Disorders v0.30 SMAD4 Paul De Fazio edited their review of gene: SMAD4: Changed rating: GREEN; Changed publications: 30071989, 25931195, 25931195, 30809044
Aortopathy_Connective Tissue Disorders v0.30 SMAD4 Paul De Fazio changed review comment from: "Limited evidence" for association with aortic dilatation/dissection by ClinGen:

"Eight genes scored as moderate (EFEMP2) or limited (ELN, FBN2, FLNA, NOTCH1,
SLC2A10, SMAD4, and SKI) for association with HTAAD. These genes are a heterogeneous group for which the evidence was often difficult to assess...the evidence, therefore, for their association with a presentation of aortic dilatation and/or dissection is often rather lacking. The other common feature of these conditions is that there is no robust evidence of progression to aortic dissection."

The ClinGen review of SMAD4, viewable in the supplementary material, dates to 22/12/2016 and so does not account for the reported individuals in PMID 30809044.

Green in PanelApp UK although with quite a few Amber reviews.

There is an association between people with with SMAD4 variants and aortic dissection (PMID 25931195).; to: "Limited evidence" for association with aortic dilatation/dissection by ClinGen:

"Eight genes scored as moderate (EFEMP2) or limited (ELN, FBN2, FLNA, NOTCH1,
SLC2A10, SMAD4, and SKI) for association with HTAAD. These genes are a heterogeneous group for which the evidence was often difficult to assess...the evidence, therefore, for their association with a presentation of aortic dilatation and/or dissection is often rather lacking. The other common feature of these conditions is that there is no robust evidence of progression to aortic dissection."


Green in PanelApp UK although with quite a few Amber reviews.

There is an association between people with with SMAD4 variants and aortic dissection (PMID 25931195). The ClinGen review of SMAD4, viewable in the supplementary material, dates to 22/12/2016 and so does not account for the reported individuals in PMID 30809044. Given this more recent data Green is appropriate.
Aortopathy_Connective Tissue Disorders v0.30 C1S Zornitza Stark Classified gene: C1S as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v0.30 C1S Zornitza Stark Gene: c1s has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.29 BGN Belinda Chong changed review comment from: 5 unrelated individuals with TAAD (PMID:27632686) plus mouse model (PMID:17502576)

PMID:27632686
Proband associated with syndromic TAAD: c.5G>A, p.Trp2*, 21 kb del: chrX:152767424-152787984 28 kb del: chrX:152768438-152795976, c.908A>C, p.Gln303Pro, c.238G>A, p.Gly80Ser. Some segregation evidence and mutation-carrying females ranged from unaffected upon repeated echocardiographic evaluation over aortic root dilatation to death due to aortic dissection.
PMID:17502576
Biglycan deficiency in male BALB/cA mice has been shown to lead to sudden death due to aortic rupture.

GEL PanelApp: As per evidence above.

ClinGen assessment uncertain due to focuses on isolated TAAD; however support involvement of BGN in syndromic TAAD: "Strong for syndromic , X-linked TAAD and “limited” for isolated TAAD. The curation shows strong assertion with syndromic TAAD. There was 1 reported proband with isolated TAAD harboring variant in this gene. Given this, the association with isolated TAAD should be limited."; to: 5 unrelated individuals with TAAD (PMID:27632686) plus mouse model (PMID:17502576)

PMID:27632686
Proband associated with syndromic TAAD: c.5G>A, p.Trp2*, 21 kb del: chrX:152767424-152787984 28 kb del: chrX:152768438-152795976, c.908A>C, p.Gln303Pro, c.238G>A, p.Gly80Ser. Some segregation evidence and mutation-carrying females ranged from unaffected upon repeated echocardiographic evaluation over aortic root dilatation to death due to aortic dissection.
PMID:17502576
Biglycan deficiency in male BALB/cA mice has been shown to lead to sudden death due to aortic rupture.

GEL PanelApp: As per evidence above.

ClinGen assessment uncertain due to focus on isolated TAAD; however support involvement of BGN in syndromic TAAD: "Strong for syndromic , X-linked TAAD and “limited” for isolated TAAD. The curation shows strong assertion with syndromic TAAD. There was 1 reported proband with isolated TAAD harboring variant in this gene. Given this, the association with isolated TAAD should be limited."
Aortopathy_Connective Tissue Disorders v0.29 PCGF2 Zornitza Stark reviewed gene: PCGF2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30343942; Phenotypes: Turnpenny-Fry syndrome, MIM#600346; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.29 TGFB3 Zornitza Stark reviewed gene: TGFB3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Aortopathy_Connective Tissue Disorders v0.29 TGFB3 Paul De Fazio changed review comment from: "Uncertain" by ClinGen. 43 patients from 11 families reported in PMID 25835445 but this seemed insufficient for the ClinGen working group.; to: "Uncertain" by ClinGen. 43 patients from 11 families with syndromic presentations of aortic aneurysms reported in PMID 25835445 but this seemed insufficient for the ClinGen working group.
Aortopathy_Connective Tissue Disorders v0.29 TGFB3 Paul De Fazio changed review comment from: "Uncertain" by ClinGen. Quite a few individuals in PMID 25835445 but this seemed insufficient for the ClinGen working group.; to: "Uncertain" by ClinGen. 43 patients from 11 families reported in PMID 25835445 but this seemed insufficient for the ClinGen working group.
Aortopathy_Connective Tissue Disorders v0.29 ABL1 Zornitza Stark reviewed gene: ABL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30071989, 28288113; Phenotypes: Congenital heart defects and skeletal malformations syndrome (MIM# 617602); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.29 TGFB3 Paul De Fazio changed review comment from: "Uncertain" by ClinGen. 3 unrelated individuals in PMID 25835445 but this was insufficient for the ClinGen working group.; to: "Uncertain" by ClinGen. Quite a few individuals in PMID 25835445 but this seemed insufficient for the ClinGen working group.
Aortopathy_Connective Tissue Disorders v0.29 FLNA Zornitza Stark Marked gene: FLNA as ready
Aortopathy_Connective Tissue Disorders v0.29 FLNA Zornitza Stark Gene: flna has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.29 FLNA Zornitza Stark Phenotypes for gene: FLNA were changed from to Heterotopia, periventricular, 1 MIM# 300049; Cardiac valvular dysplasia, X-linked MIM# 314400.
Aortopathy_Connective Tissue Disorders v0.28 FLNA Zornitza Stark Publications for gene: FLNA were set to
Aortopathy_Connective Tissue Disorders v0.27 FLNA Zornitza Stark Mode of inheritance for gene: FLNA 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)
Aortopathy_Connective Tissue Disorders v0.26 MED12 Ain Roesley reviewed gene: MED12: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 30071989, 19938245, 17369503; Phenotypes: heritable thoracic aortic aneurysm and dissection, Opitz-Kaveggia syndrome (FS syndrome), X-Linked Ohdo Syndrome (XLOS), Lujan Syndrome (LS); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Aortopathy_Connective Tissue Disorders v0.26 FLNA Naomi Baker reviewed gene: FLNA: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30071989, 29334594.; Phenotypes: Heterotopia, periventricular, 1 MIM# 300049, Cardiac valvular dysplasia, X-linked MIM# 314400.; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Aortopathy_Connective Tissue Disorders v0.26 PCGF2 Paul De Fazio changed review comment from: Not reviewed by ClinGen Aortopathy Working Group.

Not on any relevant PanelApp UK panel although green on others.

11 unrelated individuals and a pair of monozygotic twins were reported all with missense variants at proline 65. 5 individuals had aortic dilatation.; to: Not reviewed by ClinGen Aortopathy Working Group.

Not on any relevant PanelApp UK panel although green on others.

11 unrelated individuals and a pair of monozygotic twins were reported all with missense variants at proline 65 in the context of Turnpenny-Fry Syndrome. 5 individuals had aortic dilatation.
Aortopathy_Connective Tissue Disorders v0.26 BGN Belinda Chong reviewed gene: BGN: Rating: GREEN; Mode of pathogenicity: None; Publications: 30071989, 27632686, 17502576; Phenotypes: Heritable Thoracic Aortic Aneurysm and Dissection; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Aortopathy_Connective Tissue Disorders v0.26 SMAD4 Paul De Fazio edited their review of gene: SMAD4: Changed publications: 30071989, 25931195, 25931195
Aortopathy_Connective Tissue Disorders v0.26 SMAD4 Paul De Fazio changed review comment from: "Limited evidence" for association with aortic dilatation/dissection by ClinGen:

"Eight genes scored as moderate (EFEMP2) or limited (ELN, FBN2, FLNA, NOTCH1,
SLC2A10, SMAD4, and SKI) for association with HTAAD. These genes are a heterogeneous group for which the evidence was often difficult to assess...the evidence, therefore, for their association with a presentation of aortic dilatation and/or dissection is often rather lacking. The other common feature of these conditions is that there is no robust evidence of progression to aortic dissection."

The ClinGen review of SMAD4, viewable in the supplementary material, dates to 22/12/2016 and does not account for the reported individuals cited below.; to: "Limited evidence" for association with aortic dilatation/dissection by ClinGen:

"Eight genes scored as moderate (EFEMP2) or limited (ELN, FBN2, FLNA, NOTCH1,
SLC2A10, SMAD4, and SKI) for association with HTAAD. These genes are a heterogeneous group for which the evidence was often difficult to assess...the evidence, therefore, for their association with a presentation of aortic dilatation and/or dissection is often rather lacking. The other common feature of these conditions is that there is no robust evidence of progression to aortic dissection."

The ClinGen review of SMAD4, viewable in the supplementary material, dates to 22/12/2016 and so does not account for the reported individuals in PMID 30809044.

Green in PanelApp UK although with quite a few Amber reviews.

There is an association between people with with SMAD4 variants and aortic dissection (PMID 25931195).
Aortopathy_Connective Tissue Disorders v0.26 TGFBR1 Paul De Fazio changed review comment from: "Definitive" by ClinGen.

Reviewed in PMID 27879313 (176 cases with variants in TGFBR1).; to: "Definitive" by ClinGen Aortopathy working group.

Reviewed in PMID 27879313 (176 cases with variants in TGFBR1).
Aortopathy_Connective Tissue Disorders v0.26 TGFB2 Paul De Fazio changed review comment from: "Definitive" by ClinGen.

ClinGen cite PMID 22772371 which describes 4 families with variants in this gene.; to: "Definitive" by ClinGen Aortopathy Working Group.

The ClinGen Working Group cite PMID 22772371 which describes 4 families with variants in this gene.
Aortopathy_Connective Tissue Disorders v0.26 TGFB3 Paul De Fazio changed review comment from: "Uncertain" by ClinGen. 3 unrelated individuals in PMID 25835445 but insufficient for the ClinGen working group.; to: "Uncertain" by ClinGen. 3 unrelated individuals in PMID 25835445 but this was insufficient for the ClinGen working group.
Aortopathy_Connective Tissue Disorders v0.26 MYH11 Paul De Fazio edited their review of gene: MYH11: Changed rating: GREEN
Aortopathy_Connective Tissue Disorders v0.26 MYH11 Paul De Fazio reviewed gene: MYH11: Rating: ; Mode of pathogenicity: None; Publications: 30071989, 16444274, 17666408, 27081537; Phenotypes: Aortic aneurysm, familial thoracic 4, MIM#160745; Mode of inheritance: None; Current diagnostic: yes
Aortopathy_Connective Tissue Disorders v0.26 MYLK Paul De Fazio Deleted their comment
Aortopathy_Connective Tissue Disorders v0.26 MYLK Paul De Fazio edited their review of gene: MYLK: Added comment: "Definitive" by Clingen Aortopathy Working Group.

Green on PanelApp UK.

Association between variants in this gene and aortic dissection established in multiple individuals and a 5-generation family (PMID 27586135;21055718;25907466).; Changed rating: GREEN
Aortopathy_Connective Tissue Disorders v0.26 MYLK Paul De Fazio changed review comment from: "Definitive" by Clingen Aortopathy Working Group.

Green on PanelApp UK.

Association between variants in this gene and aortic dissection established in multiple individuals and a 5-generation family (PMID 27586135;21055718;25907466).; to: "Definitive" by Clingen Aortopathy Working Group.

Green on PanelApp UK.

Association between variants in this gene and aortic dissection established in multiple individuals and a 5-generation family (PMID 27586135;21055718;25907466).
Aortopathy_Connective Tissue Disorders v0.26 MYLK Paul De Fazio reviewed gene: MYLK: Rating: ; Mode of pathogenicity: None; Publications: 30071989, 27586135, 21055718, 25907466; Phenotypes: Aortic aneurysm, familial thoracic 7, MIM#600922; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Aortopathy_Connective Tissue Disorders v0.26 PCGF2 Paul De Fazio changed review comment from: Not reviewed by ClinGen Aortopathy Working Group.

Not on any relevant PanelApp UK panel.

11 unrelated individuals and a pair of monozygotic twins were reported all with missense variants at proline 65. 5 individuals had aortic dilatation.; to: Not reviewed by ClinGen Aortopathy Working Group.

Not on any relevant PanelApp UK panel although green on others.

11 unrelated individuals and a pair of monozygotic twins were reported all with missense variants at proline 65. 5 individuals had aortic dilatation.
Aortopathy_Connective Tissue Disorders v0.26 PCGF2 Paul De Fazio changed review comment from: Not reviewed by ClinGen Aortopathy Working Group.

Not on any relevant PanelApp UK panel.

11 unrelated individuals and a pair of monozygotic twins were reported all with missense variants at proline 65. 5 individuals had aortic dilatation.; to: Not reviewed by ClinGen Aortopathy Working Group.

Not on any relevant PanelApp UK panel.

11 unrelated individuals and a pair of monozygotic twins were reported all with missense variants at proline 65. 5 individuals had aortic dilatation.
Aortopathy_Connective Tissue Disorders v0.26 PCGF2 Paul De Fazio reviewed gene: PCGF2: Rating: AMBER; Mode of pathogenicity: None; Publications: 30343942; Phenotypes: Turnpenny-Fry syndrome, MIM#600346; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Aortopathy_Connective Tissue Disorders v0.26 PRKG1 Paul De Fazio reviewed gene: PRKG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30071989, 23910461, 30577811; Phenotypes: Aortic aneurysm, familial thoracic 8, MIM#176894; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Aortopathy_Connective Tissue Disorders v0.26 SKI Paul De Fazio changed review comment from: "Limited" evidence by ClinGen Aortopathy Working Group but:

"Diagnosis of Loeys-Dietz syndrome versus Shprintzen-Goldberg syndrome is thus important for correct management and risk stratification, and supports the conclusion that the gene for Shprintzen- Goldberg syndrome, SKI, should be included in diagnostic panels for characteristic syndromic presentations, especially in the pediatric setting."

>20 individuals described in the context of Shprintzen-Goldberg syndrome which can involve aortic dilatations (PMID 23023332, 24736733); to: "Limited" evidence by ClinGen Aortopathy Working Group but:

"Diagnosis of Loeys-Dietz syndrome versus Shprintzen-Goldberg syndrome is thus important for correct management and risk stratification, and supports the conclusion that the gene for Shprintzen- Goldberg syndrome, SKI, should be included in diagnostic panels for characteristic syndromic presentations, especially in the pediatric setting."

>20 individuals described in the context of Shprintzen-Goldberg syndrome which can involve aortic dilatations (PMID 23023332, 24736733)

Also Green on PanelApp UK
Aortopathy_Connective Tissue Disorders v0.26 SKI Paul De Fazio reviewed gene: SKI: Rating: GREEN; Mode of pathogenicity: None; Publications: 30071989, 23023332, 24736733; Phenotypes: Shprintzen-Goldberg syndrome, MIM#164780; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Aortopathy_Connective Tissue Disorders v0.26 SLC2A10 Paul De Fazio reviewed gene: SLC2A10: Rating: GREEN; Mode of pathogenicity: None; Publications: 30071989, 16550171, 17935213; Phenotypes: Arterial tortuosity syndrome MIM#606145; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Aortopathy_Connective Tissue Disorders v0.26 COL5A1 Ain Roesley changed review comment from: PMID: 30071989; Classified as 'No Evidence' by Clingen for heritable thoracic aortic aneurysm and dissection


Gene reviews: 75-78% of classical EDS is caused by pathogenic variants in COL5A1. Haploinsufficiency is the more common disease mechanism whoeever, missense variants in the triple helical domain of the α1(V) or α2(V) chains are likely to have dominant-negative activity.
(https://www.ncbi.nlm.nih.gov/books/NBK1244/); to: PMID: 30071989; Classified as 'No Evidence' by Clingen for heritable thoracic aortic aneurysm and dissection


GeneReviews: 75-78% of classical EDS is caused by pathogenic variants in COL5A1. Haploinsufficiency is the more common disease mechanism whoeever, missense variants in the triple helical domain of the α1(V) or α2(V) chains are likely to have dominant-negative activity.
(https://www.ncbi.nlm.nih.gov/books/NBK1244/)
Aortopathy_Connective Tissue Disorders v0.26 COL5A1 Ain Roesley reviewed gene: COL5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30071989; Phenotypes: Heritable Thoracic Aortic Aneurysm and Dissection, Classic Ehlers-Danlos Syndrome (MIM# 130000); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.26 SLC2A10 Paul De Fazio Deleted their review
Aortopathy_Connective Tissue Disorders v0.26 SLC2A10 Paul De Fazio reviewed gene: SLC2A10: Rating: RED; Mode of pathogenicity: None; Publications: 30071989; Phenotypes: Hereditary thoracic aortic aneurysm and dissection; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Aortopathy_Connective Tissue Disorders v0.26 SLC2A10 Paul De Fazio Deleted their review
Aortopathy_Connective Tissue Disorders v0.26 SLC2A10 Paul De Fazio reviewed gene: SLC2A10: Rating: RED; Mode of pathogenicity: None; Publications: 30071989; Phenotypes: Hereditary thoracic aortic aneurysm and dissection; Mode of inheritance: None
Aortopathy_Connective Tissue Disorders v0.26 COL3A1 Ain Roesley reviewed gene: COL3A1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30071989, 25758994; Phenotypes: Ehlers-Danlos syndrome, vascular type, heritable thoracic aortic aneurysm and dissection; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.26 COL1A1 Ain Roesley reviewed gene: COL1A1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30071989, 28981071; Phenotypes: Classical Ehlers-Danlos Syndrome, arthrochalasia Ehlers-Danlos Syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.26 LOX Naomi Baker reviewed gene: LOX: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30071989, 26838787, 30675029.; Phenotypes: Aortic aneurysm, familial thoracic 10 MIM#617168; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.26 SMAD3 Paul De Fazio reviewed gene: SMAD3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30071989; Phenotypes: Loeys-Dietz syndrome 3, MIM# 613795; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Aortopathy_Connective Tissue Disorders v0.26 SMAD4 Paul De Fazio changed review comment from: "Limited evidence" for association with aortic dilatation/dissection by ClinGen:

"Eight genes scored as moderate (EFEMP2) or limited (ELN, FBN2, FLNA, NOTCH1,
SLC2A10, SMAD4, and SKI) for association with HTAAD. These genes are a heterogeneous group for which the evidence was often difficult to assess...the evidence, therefore, for their association with a presentation of aortic dilatation and/or dissection is often rather lacking. The other common feature of these conditions is that there is no robust evidence of progression to aortic dissection."; to: "Limited evidence" for association with aortic dilatation/dissection by ClinGen:

"Eight genes scored as moderate (EFEMP2) or limited (ELN, FBN2, FLNA, NOTCH1,
SLC2A10, SMAD4, and SKI) for association with HTAAD. These genes are a heterogeneous group for which the evidence was often difficult to assess...the evidence, therefore, for their association with a presentation of aortic dilatation and/or dissection is often rather lacking. The other common feature of these conditions is that there is no robust evidence of progression to aortic dissection."

The ClinGen review of SMAD4, viewable in the supplementary material, dates to 22/12/2016 and does not account for the reported individuals cited below.
Aortopathy_Connective Tissue Disorders v0.26 SMAD4 Paul De Fazio reviewed gene: SMAD4: Rating: AMBER; Mode of pathogenicity: None; Publications: 30071989; Phenotypes: Hereditary thoracic aortic aneurysm and dissection; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Aortopathy_Connective Tissue Disorders v0.26 TGFB2 Paul De Fazio reviewed gene: TGFB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30071989, 22772371; Phenotypes: Loeys-Dietz syndrome 4; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Aortopathy_Connective Tissue Disorders v0.26 TGFB3 Paul De Fazio reviewed gene: TGFB3: Rating: AMBER; Mode of pathogenicity: None; Publications: 30071989, 25835445; Phenotypes: Arrhythmogenic right ventricular dysplasia 1, Loeys-Dietz syndrome 5; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Aortopathy_Connective Tissue Disorders v0.26 TGFBR1 Paul De Fazio reviewed gene: TGFBR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30071989, 27879313; Phenotypes: Loeys-Dietz syndrome 1; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Aortopathy_Connective Tissue Disorders v0.26 TGFBR2 Paul De Fazio reviewed gene: TGFBR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30071989, 27879313; Phenotypes: Loeys-Dietz syndrome 2; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Aortopathy_Connective Tissue Disorders v0.26 CBS Ain Roesley reviewed gene: CBS: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30071989, 1301198, 10408774, 7762555, 12815602, 16307898, 25455305, 26667307, 29508359; Phenotypes: Homocystinuria (MIM# 236200); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Aortopathy_Connective Tissue Disorders v0.26 C1S Ain Roesley reviewed gene: C1S: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 30071989, 27745832, 31921203; Phenotypes: Ehlers-Danlos syndrome, periodontal type, 1 (MIM# 130080); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.26 C1R Ain Roesley reviewed gene: C1R: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30071989, 27745832; Phenotypes: Ehlers-Danlos syndrome, periodontal type, 1 (MIM# 130080); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.26 ABL1 Ain Roesley reviewed gene: ABL1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 30071989, 28288113; Phenotypes: Congenital heart defects and skeletal malformations syndrome (MIM# 617602); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.26 LOX Naomi Baker Deleted their review
Aortopathy_Connective Tissue Disorders v0.26 LOX Naomi Baker reviewed gene: LOX: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Aortic aneurysm, familial thoracic 10 MIM#10617168; Mode of inheritance: None
Aortopathy_Connective Tissue Disorders v0.26 ABL1 Ain Roesley Deleted their review
Aortopathy_Connective Tissue Disorders v0.26 ACTA2 Ain Roesley reviewed gene: ACTA2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30724374; Phenotypes: hereditary thoracic aortic aneurysm and dissection; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.26 ABL1 Ain Roesley reviewed gene: ABL1: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 30071989, 28288113; Phenotypes: Congenital heart defects and skeletal malformations syndrome (MIM# 617602); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Aortopathy_Connective Tissue Disorders v0.25 EFEMP1 Zornitza Stark Marked gene: EFEMP1 as ready
Aortopathy_Connective Tissue Disorders v0.25 EFEMP1 Zornitza Stark Gene: efemp1 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.25 EFEMP1 Zornitza Stark Classified gene: EFEMP1 as Amber List (moderate evidence)
Aortopathy_Connective Tissue Disorders v0.25 EFEMP1 Zornitza Stark Gene: efemp1 has been classified as Amber List (Moderate Evidence).
Aortopathy_Connective Tissue Disorders v0.24 EFEMP1 Michelle Torres gene: EFEMP1 was added
gene: EFEMP1 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: EFEMP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EFEMP1 were set to 32006683; 31792352
Phenotypes for gene: EFEMP1 were set to EFEMP1-related connective tissue disorder
Review for gene: EFEMP1 was set to AMBER
Added comment: New gene-disease association for EFEMP1: truncating variants (absent in gnomAD):

PMID 31792352 reports one man with a pronounced connective tissue phenotype presenting multiple and recurrent abdominal and thoracic herniae, myopia, hypermobile joints, scoliosis, and thin translucent skin. This individual has no clinical signs of retinal dystrophy.

PMID 32006683 reports 2 homozygous siblings (consanguinous) with multiple and recurrent herniae, pelvic and rectal prolapse, huge diverticula, marfanoid habitus, joint laxity, dorsal scoliosis, advanced bone age, pectus excavatum, dysmorphic facial features, and myopia. Both were homozygous for a truncating in VCPKMT, with no gene-disease association in OMIM, not in Panel App.

Both papers mention that studies on EFEMP1−/− mice revealed a phenotypic resemblance.
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.24 Bryony Thompson Panel types changed to Victorian Clinical Genetics Services; Royal Melbourne Hospital; Rare Disease
Aortopathy_Connective Tissue Disorders v0.23 SMAD4 Zornitza Stark Marked gene: SMAD4 as ready
Aortopathy_Connective Tissue Disorders v0.23 SMAD4 Zornitza Stark Gene: smad4 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.23 SMAD4 Zornitza Stark Classified gene: SMAD4 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.23 SMAD4 Zornitza Stark Gene: smad4 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.22 SMAD4 Zornitza Stark gene: SMAD4 was added
gene: SMAD4 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: SMAD4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMAD4 were set to 30809044
Phenotypes for gene: SMAD4 were set to Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, MIM# 175050; Thoracic aortic aneurysm
Review for gene: SMAD4 was set to GREEN
Added comment: SMAD4 pathogenic variants cause juvenile polyposis (JPS) and hereditary hemorrhagic telangiectasia (HHT), and 40% of affected individuals also have thoracic aortic disease. Three individuals recently reported with rare/novel missense and isolated thoracic aortic aneurysm.
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.21 AEBP1 Zornitza Stark Marked gene: AEBP1 as ready
Aortopathy_Connective Tissue Disorders v0.21 AEBP1 Zornitza Stark Gene: aebp1 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.21 AEBP1 Zornitza Stark Phenotypes for gene: AEBP1 were changed from Ehlers-Danlos syndrome, classic-like, 2, MIM# 618000 to Ehlers-Danlos syndrome, classic-like, 2, MIM# 618000
Aortopathy_Connective Tissue Disorders v0.21 AEBP1 Zornitza Stark Phenotypes for gene: AEBP1 were changed from to Ehlers-Danlos syndrome, classic-like, 2, MIM# 618000
Aortopathy_Connective Tissue Disorders v0.20 AEBP1 Zornitza Stark Publications for gene: AEBP1 were set to
Aortopathy_Connective Tissue Disorders v0.19 AEBP1 Zornitza Stark Mode of inheritance for gene: AEBP1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Aortopathy_Connective Tissue Disorders v0.18 SMAD2 Zornitza Stark Marked gene: SMAD2 as ready
Aortopathy_Connective Tissue Disorders v0.18 SMAD2 Zornitza Stark Gene: smad2 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.18 SMAD2 Zornitza Stark Classified gene: SMAD2 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.18 SMAD2 Zornitza Stark Gene: smad2 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.17 SMAD2 Zornitza Stark gene: SMAD2 was added
gene: SMAD2 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature
Mode of inheritance for gene: SMAD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SMAD2 were set to 29967133
Phenotypes for gene: SMAD2 were set to Aortic and arterial aneurysmal disease; connective tissue disease
Review for gene: SMAD2 was set to GREEN
Added comment: 9 individuals from 5 families with wide spectrum of autosomal dominant aortic and arterial aneurysmal disease combined with connective tissue disease similar to Marfan syndrome and Loeys-Dietz syndrome.
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.16 SMAD3 Zornitza Stark Marked gene: SMAD3 as ready
Aortopathy_Connective Tissue Disorders v0.16 SMAD3 Zornitza Stark Gene: smad3 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.16 SMAD3 Zornitza Stark Phenotypes for gene: SMAD3 were changed from to Loeys-Dietz syndrome 3, MIM# 613795
Aortopathy_Connective Tissue Disorders v0.15 SMAD3 Zornitza Stark Publications for gene: SMAD3 were set to
Aortopathy_Connective Tissue Disorders v0.14 AEBP1 Kristin Rigbye reviewed gene: AEBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29606302, 30668708, 30548383, 30759870; Phenotypes: Ehlers-Danlos Syndrome (EDS); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Aortopathy_Connective Tissue Disorders v0.14 SMAD3 Zornitza Stark Mode of inheritance for gene: SMAD3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.13 SMAD3 Zornitza Stark reviewed gene: SMAD3: Rating: GREEN; Mode of pathogenicity: None; Publications: 21217753, 30661052; Phenotypes: Loeys-Dietz syndrome 3, MIM# 613795; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.13 FBN2 Zornitza Stark Marked gene: FBN2 as ready
Aortopathy_Connective Tissue Disorders v0.13 FBN2 Zornitza Stark Gene: fbn2 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.13 FBN2 Zornitza Stark Phenotypes for gene: FBN2 were changed from to Contractural arachnodactyly, congenital, MIM# 121050
Aortopathy_Connective Tissue Disorders v0.12 FBN2 Zornitza Stark Mode of inheritance for gene: FBN2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.11 FBN2 Zornitza Stark edited their review of gene: FBN2: Changed phenotypes: Contractural arachnodactyly, congenital, MIM# 121050
Aortopathy_Connective Tissue Disorders v0.11 FBN2 Zornitza Stark reviewed gene: FBN2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Macular degeneration, early-onset, MIM# 616118; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Aortopathy_Connective Tissue Disorders v0.11 FBN1 Melanie Marty reviewed gene: FBN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29357934; Phenotypes: Acromicric dysplasia (102370), Ectopia lentis, familial (129600), Geleophysic dysplasia 2 (614185), Marfan lipodystrophy syndrome (616914), Marfan syndrome (154700), MASS syndrome (604308), Stiff skin syndrome (184900), Weill-Marchesani syndrome 2, dominant (608328); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Aortopathy_Connective Tissue Disorders v0.11 Zornitza Stark Panel name changed from Aortopathy_Connective tissue disorders to Aortopathy_Connective Tissue Disorders
Panel types changed to Victorian Clinical Genetics Services; Rare Disease
Aortopathy_Connective Tissue Disorders v0.10 Zornitza Stark Panel name changed from Aortopathy, Connective tissue disorder_VCGS to Aortopathy_Connective tissue disorders
Panel types changed to Victorian Clinical Genetics Services
Aortopathy_Connective Tissue Disorders v0.9 ROBO4 Zornitza Stark Marked gene: ROBO4 as ready
Aortopathy_Connective Tissue Disorders v0.9 ROBO4 Zornitza Stark Gene: robo4 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.9 ROBO4 Zornitza Stark Classified gene: ROBO4 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.9 ROBO4 Zornitza Stark Gene: robo4 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.8 ROBO4 Sue White gene: ROBO4 was added
gene: ROBO4 was added to Aortopathy, Connective tissue disorder_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: Sources: Literature
Aortopathy_Connective Tissue Disorders v0.7 PLOD3 Zornitza Stark Marked gene: PLOD3 as ready
Aortopathy_Connective Tissue Disorders v0.7 PLOD3 Zornitza Stark Gene: plod3 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.7 PLOD3 Zornitza Stark Classified gene: PLOD3 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.7 PLOD3 Zornitza Stark Gene: plod3 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.5 PLOD3 Zornitza Stark gene: PLOD3 was added
gene: PLOD3 was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Literature
Mode of inheritance for gene: PLOD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLOD3 were set to 18834968; 31129566; 30237576; 30463024
Phenotypes for gene: PLOD3 were set to Lysyl hydroxylase 3 deficiency, MIM#612394
Review for gene: PLOD3 was set to GREEN
Added comment: At least three families reported with bi-allelic variants in this gene and a connective tissue phenotype; another in a large study reporting multiple emerging genes in consanguineous families.
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.5 PLOD3 Zornitza Stark gene: PLOD3 was added
gene: PLOD3 was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Literature
Mode of inheritance for gene: PLOD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLOD3 were set to 18834968; 31129566; 30237576; 30463024
Phenotypes for gene: PLOD3 were set to Lysyl hydroxylase 3 deficiency, MIM#612394
Review for gene: PLOD3 was set to GREEN
Added comment: At least three families reported with bi-allelic variants in this gene and a connective tissue phenotype; another in a large study reporting multiple emerging genes in consanguineous families.
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.4 NPR3 Zornitza Stark Marked gene: NPR3 as ready
Aortopathy_Connective Tissue Disorders v0.4 NPR3 Zornitza Stark Gene: npr3 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.4 NPR3 Zornitza Stark Classified gene: NPR3 as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.4 NPR3 Zornitza Stark Gene: npr3 has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.3 NPR3 Zornitza Stark gene: NPR3 was added
gene: NPR3 was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Literature
Mode of inheritance for gene: NPR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NPR3 were set to 30032985
Phenotypes for gene: NPR3 were set to Tall stature, skeletal abnormalities, aortic dilatation
Review for gene: NPR3 was set to GREEN
Added comment: 4 individuals from three unrelated families.
Sources: Literature
Aortopathy_Connective Tissue Disorders v0.2 ATP7A Zornitza Stark Marked gene: ATP7A as ready
Aortopathy_Connective Tissue Disorders v0.2 ATP7A Zornitza Stark Gene: atp7a has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.2 ATP7A Zornitza Stark Classified gene: ATP7A as Green List (high evidence)
Aortopathy_Connective Tissue Disorders v0.2 ATP7A Zornitza Stark Gene: atp7a has been classified as Green List (High Evidence).
Aortopathy_Connective Tissue Disorders v0.1 ATP7A Zornitza Stark gene: ATP7A was added
gene: ATP7A was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert list
Mode of inheritance for gene: ATP7A was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: ATP7A were set to Occipital horn syndrome, MIM#304150; Menkes disease, MIM#309400
Review for gene: ATP7A was set to GREEN
Added comment: Connective tissue laxity is a prominent part of the phenotype.
Sources: Expert list
Aortopathy_Connective Tissue Disorders v0.0 TGFBR2 Zornitza Stark gene: TGFBR2 was added
gene: TGFBR2 was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: TGFBR2 was set to Unknown
Aortopathy_Connective Tissue Disorders v0.0 TGFBR1 Zornitza Stark gene: TGFBR1 was added
gene: TGFBR1 was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: TGFBR1 was set to Unknown
Aortopathy_Connective Tissue Disorders v0.0 TGFB3 Zornitza Stark gene: TGFB3 was added
gene: TGFB3 was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: TGFB3 was set to Unknown
Aortopathy_Connective Tissue Disorders v0.0 TGFB2 Zornitza Stark gene: TGFB2 was added
gene: TGFB2 was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: TGFB2 was set to Unknown
Aortopathy_Connective Tissue Disorders v0.0 SMAD3 Zornitza Stark gene: SMAD3 was added
gene: SMAD3 was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: SMAD3 was set to Unknown
Aortopathy_Connective Tissue Disorders v0.0 SLC2A10 Zornitza Stark gene: SLC2A10 was added
gene: SLC2A10 was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: SLC2A10 was set to Unknown
Aortopathy_Connective Tissue Disorders v0.0 SKI Zornitza Stark gene: SKI was added
gene: SKI was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: SKI was set to Unknown
Aortopathy_Connective Tissue Disorders v0.0 PRKG1 Zornitza Stark gene: PRKG1 was added
gene: PRKG1 was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: PRKG1 was set to Unknown
Aortopathy_Connective Tissue Disorders v0.0 PCGF2 Zornitza Stark gene: PCGF2 was added
gene: PCGF2 was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: PCGF2 was set to Unknown
Aortopathy_Connective Tissue Disorders v0.0 MYLK Zornitza Stark gene: MYLK was added
gene: MYLK was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: MYLK was set to Unknown
Aortopathy_Connective Tissue Disorders v0.0 MYH11 Zornitza Stark gene: MYH11 was added
gene: MYH11 was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: MYH11 was set to Unknown
Aortopathy_Connective Tissue Disorders v0.0 MED12 Zornitza Stark gene: MED12 was added
gene: MED12 was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: MED12 was set to Unknown
Aortopathy_Connective Tissue Disorders v0.0 LOX Zornitza Stark gene: LOX was added
gene: LOX was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: LOX was set to Unknown
Aortopathy_Connective Tissue Disorders v0.0 FLNA Zornitza Stark gene: FLNA was added
gene: FLNA was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: FLNA was set to Unknown
Aortopathy_Connective Tissue Disorders v0.0 FBN2 Zornitza Stark gene: FBN2 was added
gene: FBN2 was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: FBN2 was set to Unknown
Aortopathy_Connective Tissue Disorders v0.0 FBN1 Zornitza Stark gene: FBN1 was added
gene: FBN1 was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: FBN1 was set to Unknown
Aortopathy_Connective Tissue Disorders v0.0 COL5A1 Zornitza Stark gene: COL5A1 was added
gene: COL5A1 was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: COL5A1 was set to Unknown
Aortopathy_Connective Tissue Disorders v0.0 COL3A1 Zornitza Stark gene: COL3A1 was added
gene: COL3A1 was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: COL3A1 was set to Unknown
Aortopathy_Connective Tissue Disorders v0.0 COL1A1 Zornitza Stark gene: COL1A1 was added
gene: COL1A1 was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: COL1A1 was set to Unknown
Aortopathy_Connective Tissue Disorders v0.0 CBS Zornitza Stark gene: CBS was added
gene: CBS was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: CBS was set to Unknown
Aortopathy_Connective Tissue Disorders v0.0 C1S Zornitza Stark gene: C1S was added
gene: C1S was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: C1S was set to Unknown
Aortopathy_Connective Tissue Disorders v0.0 C1R Zornitza Stark gene: C1R was added
gene: C1R was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: C1R was set to Unknown
Aortopathy_Connective Tissue Disorders v0.0 BGN Zornitza Stark gene: BGN was added
gene: BGN was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: BGN was set to Unknown
Aortopathy_Connective Tissue Disorders v0.0 AEBP1 Zornitza Stark gene: AEBP1 was added
gene: AEBP1 was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: AEBP1 was set to Unknown
Aortopathy_Connective Tissue Disorders v0.0 ACTA2 Zornitza Stark gene: ACTA2 was added
gene: ACTA2 was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: ACTA2 was set to Unknown
Aortopathy_Connective Tissue Disorders v0.0 ABL1 Zornitza Stark gene: ABL1 was added
gene: ABL1 was added to Aortopathy, Connective tissue disorder_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: ABL1 was set to Unknown
Aortopathy_Connective Tissue Disorders v0.0 Zornitza Stark Added panel Aortopathy, Connective tissue disorder_VCGS