Sequencing of NOTCH1, GATA5, TGFBR1 and TGFBR2genes in familial cases of bicuspid aortic valve

Abstract

BackgroundThe purpose of our study was to investigate the potential contribution of germline mutations in NOTCH1, GATA5 and TGFBR1 and TGFBR2 genes in a cohort of Italian patients with familial Bicuspid Aortic Valve (BAV).MethodsAll the coding exons including adjacent intronic as well as 5′ and 3′ untranslated (UTR) sequences of NOTCH1, GATA5, TGFBR1 and TGFBR2 genes were screened by direct gene sequencing in 11 index patients (8 males; age = 42 ± 19 years) with familial BAV defined as two or more affected members.ResultsTwo novel mutations, a missense and a nonsense mutation (Exon 5, p.P284L; Exon 26, p.Y1619X), were found in the NOTCH1 gene in two unrelated families. The mutations segregated with the disease in these families, and they were not found on 200 unrelated chromosomes from ethnically matched controls. No pathogenetic mutation was identified in GATA5, TGFBR1 and TGFBR2 genes.ConclusionsTwo novel NOTCH1 mutations were identified in two Italian families with BAV, highlighting the role of a NOTCH1 signaling pathway in BAV and its aortic complications. These findings are of relevance for genetic counseling and clinical care of families presenting with BAV. Future studies are needed in order to unravel the still largely unknown genetics of BAV.

Bicuspid aortic valve syndrome: a multidisciplinary approach for a complex entity

“…Mutations in NOTCH1 were reported to segregate with affected patients in a five-generation European-American family and, in addition, in a second and smaller Hispanic family (33). Following this study, mutations in NOTCH1 were described among patients with sporadic BAV and concomitant TAAs in several subsequent studies (34).…”

Etiology of Valvular Heart Disease

“…Subsequently, NOTCH1 mutations have been found in other individuals and families with aortic valve disease. 49, 50 Further support of this link was the identification that mice haplo-insufficient for Notch1 in the setting of endothelial nitric oxide synthase (Nos3) deletion display a near 100% penetrance of BAV as compared with the lower incidence (~25-30%) of BAV in Nos3 −/− mice. 51 Recently, deletion of Gata5, a zinc finger transcription factor, in the valve endothelium was found to result in a partially penetrant right-noncoronary BAV phenotype in mice, with associated dysregulation of the Notch signaling pathway in the developing OFT.…”

Bicuspid aortic valve disease

“…(17) Several other genes have been associated with BAV, including mutations in GATA5, TGFBR1 and TGFBR2. (18,19) Likely related to the complexities of BAV inheritance patterns and variable classification schemes, a clear single gene basis for the BAV phenotype has not been clearly established; it is plausible that the BAV syndrome is actually a complex multifactorial manifestation of both environmental and genetic issues.…”