Whole exome sequencing for the identification of a new mutation in TGFB2 involved in a familial case of non-syndromic aortic disease

Abstract Background Non-syndromic aortic disease (NSAD) is a frequently asymptomatic but potentially lethal disease characterised by familial cases of thoracic aortic aneurysms and dissections. This monogenic but genetically heterogeneous condition is primarily inherited as an autosomal dominant disorder with low penetrance and variable expression. Mutations in ACTA2 , TGFBR1 , TGFBR2 , MYH11 , SMAD3 , MYLK , and FBN1 genes have been described but still, there are many unresolved familial cases. Methods The whole exome of two distantly related and affected members of a Spanish family with multiple cases of NSAD was analysed through 5500 SOLiD ™ System for the identification of shared and putative pathogenic variants. Results A new mutation termed c.C1042T:p.R348C ( NM_001135599.2 ) was identified in TGFB2 , a gene located in an evolutionary highly conserved region (Chr1: 218,519,577-218,617,961) that has been recently connected to this disease. The analysis of other family members using capillary sequencing confirmed cosegregation of the mutation with the disease and its incomplete penetrance. Conclusions The repeated implication of TGFB2 in the development of thoracic aortic aneurysms and dissections suggests that this gene should be considered during genetic diagnosis of this disease. An accurate diagnosis of affected individuals and additional family members at risk allows for a personalised and more efficient gene-based follow-up and treatment. Finally, the reiterative presence of common musculoskeletal and craniofacial additional features in patients with TGFB2 mutations suggests the existence of a new yet undefined connective tissue syndrome responsible for not only aortic dilation, but also for the other extracardiac alterations present in the affected patients.