Phenotypic and genotypic approach of a large family with early onset tricuspid aortic valve sclerosis-stenosis: A multimodality evaluation

Aortic valve sclerosis-stenosis (AVS) is regarded a consequence of cardiovascular risk and genetic factors. Severe AVS is a significant cause of morbidity and mortality in 5% of individuals over 65 years of age. Despite previous attempts, little is known about genetics of AVS. We aimed to study genetic and non-genetic determinants of AVS in a large family with little cardiovascular risk factors. We identified a 5 generations large family of AVS. We proposed a screening to all relatives with clinical, biological and echocardiography assessment. Aortic valve (AV) calcium score was evaluated by CT scan. Biological assessment comprised especially DNA extraction for Next Generation Sequencing. The family comprises >100 relatives. To date 34 members (53.1 ± 14.7 years, 17 males) have been screened, 15 are affected (59.6 ± 10.8 years) and 19 non-affected (46.3 ± 13.6, P n  = 6, 17.6%) was greater in affected members ( P P  = 0.05) and AV calcium was score greater (88.4 ± 199 vs. 0 UH) in affected members. High rate genotyping of 20 individuals allowed us to identify a common IBD (Identity By Descendance) region for all affected members on chromosome 5(rs4129875 to rs31619). Whole genome analysis was carried out in 4 cousins allowing the identification of 18 rare functional variants shared by at least 3 out of 4 sequenced individuals. Preliminary phenotypic and genetic approach of a large family of AVS reports a homogeneous and unique clinical portrait with early onset tricuspid AVS and fusiform aorta. While specific gene remains to be identified, IBD found a chromosome 5 region associated with AVS ( Fig. 1 ).