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Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms.

ABSTRACT: Thoracic aortic aneurysms leading to acute aortic dissections (TAAD) can be inherited in families in an autosomal dominant manner. As part of the spectrum of clinical heterogeneity of familial TAAD, we recently described families with multiple members that had TAAD and intracranial aneurysms or TAAD and intracranial and abdominal aortic aneurysms inherited in an autosomal dominant manner.To identify the causative mutation in a large family with autosomal dominant inheritance of TAAD with intracranial and abdominal aortic aneurysms by performing exome sequencing of 2 distantly related individuals with TAAD and identifying shared rare variants.A novel frame shift mutation, p. N218fs (c.652delA), was identified in the SMAD3 gene and segregated with the vascular diseases in this family with a logarithm of odds score of 2.52. Sequencing of 181 probands with familial TAAD identified 3 additional SMAD3 mutations in 4 families, p.R279K (c.836G>A), p.E239K (c.715G>A), and p.A112V (c.235C>T), resulting in a combined logarithm of odds score of 5.21. These 4 mutations were notably absent in 2300 control exomes. SMAD3 mutations were recently described in patients with aneurysms osteoarthritis syndrome and some of the features of this syndrome were identified in individuals in our cohort, but these features were notably absent in many SMAD3 mutation carriers.SMAD3 mutations are responsible for 2% of familial TAAD. Mutations are found in families with TAAD alone, along with families with TAAD, intracranial aneurysms, abdominal aortic and bilateral iliac aneurysms segregating in an autosomal dominant manner.

SUBMITTER: Regalado ES

PROVIDER: S-EPMC4115811 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms.

Regalado Ellen S ES Guo Dong-Chuan DC Villamizar Carlos C Avidan Nili N Gilchrist Dawna D McGillivray Barbara B Clarke Lorne L Bernier Francois F Santos-Cortez Regie L RL Leal Suzanne M SM Bertoli-Avella Aida M AM Shendure Jay J Rieder Mark J MJ Nickerson Deborah A DA Milewicz Dianna M DM

Circulation research 20110721 6

<h4>Rationale</h4>Thoracic aortic aneurysms leading to acute aortic dissections (TAAD) can be inherited in families in an autosomal dominant manner. As part of the spectrum of clinical heterogeneity of familial TAAD, we recently described families with multiple members that had TAAD and intracranial aneurysms or TAAD and intracranial and abdominal aortic aneurysms inherited in an autosomal dominant manner.<h4>Objective</h4>To identify the causative mutation in a large family with autosomal domin ...[more]

PMID: 21778426

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Project description:BackgroundThoracic aortic aneurysms progressively enlarge and predispose to acute aortic dissections. Up to 25% of individuals with thoracic aortic disease harbor an underlying Mendelian pathogenic variant. An evidence-based strategy for selection of genes to test in hereditary thoracic aortic aneurysm and dissection (HTAAD) helps inform family screening and intervention to prevent life-threatening thoracic aortic events.ObjectivesThe purpose of this study was to accurately identify genes that predispose to HTAAD using the Clinical Genome Resource (ClinGen) framework.MethodsWe applied the semiquantitative ClinGen framework to assess presumed gene-disease relationships between 53 candidate genes and HTAAD. Genes were classified as causative for HTAAD if they were associated with isolated thoracic aortic disease and were clinically actionable, triggering routine aortic surveillance, intervention, and family cascade screening. All gene-disease assertions were evaluated by a pre-defined curator-expert pair and subsequently discussed with an expert panel.ResultsGenes were classified based on the strength of association with HTAAD into 5 categories: definitive (n = 9), strong (n = 2), moderate (n = 4), limited (n = 15), and no reported evidence (n = 23). They were further categorized by severity of associated aortic disease and risk of progression. Eleven genes in the definitive and strong groups were designated as "HTAAD genes" (category A). Eight genes were classified as unlikely to be progressive (category B) and 4 as low risk (category C). The remaining genes were recent genes with an uncertain classification or genes with no evidence of association with HTAAD.ConclusionsThe ClinGen framework is useful to semiquantitatively assess the strength of gene-disease relationships for HTAAD. Gene categories resulting from the curation may inform clinical laboratories in the development, interpretation, and subsequent clinical implications of genetic testing for patients with aortic disease.

Dataset Information

Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms.

Publications

Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms.

Similar Datasets

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