Is bicuspid aortic valve morphology genetically determined? A family-based study and systematic literature review

Introduction: Bicuspid aortic valve (BAV) is common congenital heart disease, with a tenfold higher prevalence among first-degree relatives of an index case. BAV has different phenotypes based on the valve’s cusp fusion pattern, and these patterns are associated with diverse clinical courses and prognoses. However, the degree to which genetic factors determine the valve morphology in BAV patients is unknown. Here, we evaluate the role of genetics in valve morphology pattern using a familial cohort.

Methods: We screened BAV patients and their first-degree relatives from two referral medical centers between 2010-2020. Phenotypes were defined by echocardiography according to Sievers classification. We calculated the concordance in BAV type between family members, comparing it to the concordance expected by chance according to the type`s prevalence using the binomial test. We then performed a systematic literature review to identify additional reports on BAV morphology within families and calculated the overall concordance rate.

Result and discussion: During the study period, 71 cases from 31 families and 327 sporadic cases were identified. BAV was diagnosed in 14.1% of the screened relatives. Among BAV families, the proportions of the different types were: 12.3% for type 0, 66.2% for type 1-LR, 15.4% for type 1-RN, 4.6% for type 1-NL, and 1.5% for type 2. Discordance between BAV phenotypes within first-degree relatives in our cohort was found in 42.9% of the families, and in 38.4% in the literature review. The concordance between BAV types within families was not significantly higher than expected by chance.

Conclusion: We demonstrated interfamilial variability in BAV morphology, while the overall concordance levels did not differ from those expected if valve morphology is entirely environmentally dictated, suggesting that morphology has a multifactorial derivation. As prognosis differs by morphology, our findings imply that pathogenesis may vary even between first-degree relatives.