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

Abstract

Rationale: 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.

Objective: 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.

Methods and results: 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.

Conclusions: 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.

Figure 1. Pedigrees of FTAAD families with SMAD3 mutations

(A) Pedigree of TAA549 that was used for exome sequencing assay. (B) Additional FTAAD pedigrees with SMAD3 mutations. Filled symbols indicate individuals with arterial aneurysms (black- thoracic aortic aneurysm and/or dissection, red- intracranial aneurysm or subarachnoid hemorrhage, green- abdominal aortic aneurysm, blue- iliac artery aneurysm, gray- sudden death without a known cause). Members of TAA549 who underwent exome sequencing are circled. A # symbol indicates individuals with osteoarthritis or other joint degenerative disease, a * symbol indicates the individual who died of unrelated causes, and a horizontal line above the symbol indicates the individual was examined by a clinical geneticist.

Figure 2. Location and conservation of SMAD3 mutations

(A) Schematic of the SMAD3 gene shows the location of novel SMAD3 variants identified in FTAAD families. The p.A112V alteration was identified in exon 2 encoding the MH1 domain involved in DNA binding. A frame shift mutation (p.N218fs) was identified in exon 5 leading to premature termination of protein translation and likely to nonsense mediated decay of the RNA. Two additional mutations, p.E239K and p.R279K, were found in exons encoding the MH2 protein-protein binding domain. (B) Orthologue conservation of the SMAD3 protein sequences involving and surrounding the missense mutations identified in the MH1 and MH2 domains.