P6501Recurrent genetic aberrations in bicuspid aortic valve disease patients with isolated severe aortic regurgitation

Abstract

Abstract Background The etiology of bicuspid aortic valve disease (BAVD) is still unclear. Recent studies have demonstrated elevated prevalence of genetic defects in BAV patients with root phenotype, which includes aortic regurgitation and root-predominant dilatation. Purpose The present study intended to illustrate the feature of genetic defects among early-onset BAV patients with isolated severe aortic regurgitation. Methods From June 2015 to December 2017, whole exome sequencing was performed upon 27 BAVD patients with isolated severe aortic regurgitation under 45 years in our institution. Patients were categorized into right-left (R-L, n=16) and non-RL (n=11) cusp fusion types, and those with complex cardiac defects were excluded from the present study. Results Among 27 patients with a median age of 30.5 (18–44) years, only one was female with a rare left-non-coronary cusp fusion type. The prevalence of root phenotype was markedly higher in RL patients (56.3% vs 9.1%, p=0.018). In RL patients, the numbers of rare genetic variants (RGVs) were 15 in extracellular matrix genes, 8 in TGF-β signaling pathway genes, 2 in smooth muscle cell contraction apparatus genes, and 3 in familiar BAV related genes. In non-RL patients, the number of RGVs were 15, 3, 4, and 5, respectively. On the other hand, the number of RGVs in above gene clusters were 9, 6, 3, 2 in patients with a root phenotype, and 21, 5, 3, 6 in those without. Eight recurrent genetic variants were identified in 6 genes (see Table). An interesting observation was that ADAMTS2 variants were exclusively found among non-RL patients without root phenotype, as FBN2 variants among RL patients with root phenoype. Recurrent Rare Genetic Variants Gene Reference sequence Variant 1000G 1000G-East Asia Patients TGFBR2 NM_001024847.2 p.Val216Ile/c.646G>A 0.004 0.018 A16, A23 TGFBR2 NM_001024847.2 p.Thr340Met/c.1019C>T 0.003 0.015 A03, A05, A07 ADAMTS2 NM_014244.4 p.Gly1169Val/c.3506G>T 0.0044 0.021 A03, A15 FBN2 NM_001999.3 p.Gly475Val/c.1424G>T 0.0004 0.002 A19, A24 ELN NM_001278939.1 p.Pro93Leu/c.278C>T 0.0014 0.0069 A22, A26 COL4A5 NM_033380.2 p.Gly953Val/c.2858G>T 0.0079 0.03 A11, A17 MYLK NM_053025.3 p.Ser243Trp/c.728C>G 0.0002 0.001 A01, A02 MYLK NM_053025.3 p.Asp717Tyr/c.2149G>T 0.0024 0.011 A04, A21 Conclusion Recurrent genetic variants could be identified in a cohort of early-onset BAVD patients with isolated severe aortic regurgitation and staggering male predominance. The incidence and clinical relevance of these variants should be validated in an extended real-world BAV cohort.