Abstrakt
Aim: Analysis of the genetic basis in a representative cohort of Czech patients with familiar bicuspid aortic valve (BAV) with / without aortic aneurysm (MIM# 109730). Materials and Methods: Altogether 100 unrelated cases were clinically examined, underwent genetic counselling and positive cases were subjected to "cascade screening" of first-degree relatives.
Massively parallel sequencing (MiSeq platform; Illumina.com) was utilised for a custom-made panel comprising either 136, 229 or 100 cardiac/aortic conditions-related candidate genes (Sophia Genetics.com). Presence of pathogenic variants was validated by Sanger sequencing and via their segregation in respective families.
Results: Pathogenic/likely pathogenic variant (ACMG Class >= 4) were found in 3/100 patients (3 %) within TGFB2, SMAD6 and FBN1. Variants of unknown significance (Class 3) were detected in 9/100 patients (9 %) comprising genes FLNA, FBN1, MYH11, TAB2, TGFB2 and GATA5.
A family with concurrent familial dilated cardiomyopathy, BAV and ectopia lentis was analysed as well. Likely causative DNA variants in MYBPC3 and FBN1 were identified, but FBN1 variants did not co-segregate with BAV.
Conclusion: The yield of genetic testing in familial forms of BAV is rather low in our cohort. Moreover, the identification of pathogenic variant in BAV-related gene is not a guarantee of their causality, hence detected variants should be carefully interpreted.
The genetic basis for the familial forms of BAV will be further studied, e.g. by whole exome analysis together with improved clinical stratification of our patient cohort.