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| Aortopathy_Connective Tissue Disorders v1.97 | ADAMTS6 |
Chirag Patel gene: ADAMTS6 was added gene: ADAMTS6 was added to Aortopathy_Connective Tissue Disorders. Sources: Literature Mode of inheritance for gene: ADAMTS6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ADAMTS6 were set to PMID: 40657314 Phenotypes for gene: ADAMTS6 were set to Aortic aneurysm MONDO:0005160; Connective tissue disorder MONDO:0003900; Congenital heart disease MONDO:0005453 Review for gene: ADAMTS6 was set to GREEN Added comment: 4 unrelated individuals with thoracic aortic dilatation/aneurysm (3/4), congenital heart defect (3/4), high palate (3/4), hypertelorism (3/4), flat feet (3/4). learning issues/ID (2/4). WES/WGS identified 4 rare predicted deleterious missense variants in ADAMTS6 gene [p.(Leu814Arg), p.(Asp319Asn), p.(Ala147Thr), p.(Ile810Leu)]. 2/4 variants were de novo, 1/4 was inherited (no parental phenotype info), 1/4 unknown status. Note: THSD4 gene, encoding ADAMTSL6, is associated with aortopathy disorder. Functional studies (patient-derived fibroblasts) demonstrated that the variants impair ADAMTS6 secretion or function resulting in increased deposition of FBN1 and FBN2, and therefore extracellular matrix accumulation and microfibril disorganization. One variant, p.(Leu814Arg), further disrupted the Hippo and TGFβ signalling pathways and altered cell adhesion. Adamts6 (S149R/S149R) mice showed ventricular septal defects and accumulation of FBN1 and FBN2 in the outflow tracts. Proposed name of condition: CHAN syndrome (Connective tissue, Heart defect, thoracic Aortic aneurysm, and Neurodevelopmental) syndrome. Sources: Literature |
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| 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 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 | 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 v0.13 | 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 v0.0 | 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 |
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