Genetic variants in families with bicuspid aortic valve diagnosed in a population cohort study

Abstract

Bicuspid aortic valve (BAV) affects 0.8% of the population and demonstrates high heritability with up to 89% of the variation in the trait being determined by genetic factors, yet the clinical utility of familial screening and genetic testing in unselected cohorts remains poorly defined/examined. Current European guidelines recommend echocardiographic screening of first-degree relatives (Class I), while genetic testing is typically reserved for syndromic presentations and cases with familial aggregation. To determine the prevalence of BAV and aortopathy among first-degree relatives of probands diagnosed neonatally in a population study, and to assess the diagnostic yield and clinical relevance of targeted genetic testing in this cohort. We prospectively enrolled families to probands diagnosed with BAV through a population study. All first-degree relatives underwent standardized echocardiography. Aortopathy was defined as ascending aortic diameters exceeding BSA-indexed reference values (adults) or z-scores ≥2 (children). Probands underwent targeted next-generation sequencing of 30 genes involved in cardiac development. Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. First-degree relatives of probands with pathogenic/likely pathogenic variants or variants of uncertain significance (VUS) (ACMG class 3-5) underwent cascade Sanger sequencing. Among 256 first-degree relatives to 87 probands, 55 (21.5%) had BAV (n=22), isolated aortopathy (n=25), or both (n=8), with 43/87 families (49.4%) demonstrating familial aggregation. Genetic testing identified ACMG class 3-5 variants in 22/87 probands (25.3%), comprising 24 different variants (14 novel) across 12 genes, including one de novo variant. The majority of the variants (n=22, 91.7%) were classified as VUS (class 3), none as likely pathogenic (class 4), and two (8.3%) as pathogenic (class 5). NOTCH1 variants were most frequent (n=7, 29.2%). Cascade genetic testing of 63 relatives for the family-specific variant identified 27 variant carriers (42.9%), of whom 9 (33.3%) had BAV and/or aortopathy. Notably, overall echocardiographic yield was similar in families with (25.4%) versus without (20.2%) identified genetic class 3-5 variants (p=0.45). Nearly half of patients with BAV had affected family members. Although one in four of the probands carried a ACMG class 3–5 variant, the predominance of VUS limits current clinical utility. The overall echocardiographic yield was similar in families with (25%) and without (20%) genetic variants but was higher in individuals carrying a variant (33%). These findings reinforce the role of echocardiographic screening of first-degree relatives and highlight the need for improved genetic discovery to enhance risk stratification in BAV.