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| 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 v1.39 | 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 |
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| 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 |
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| 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 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 v0.30 | 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. |
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| 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). |
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| 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 |
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| 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 | 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. |
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| 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 |
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| 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 v0.0 | 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 |
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