A genotype-first approach to exploring Mendelian cardiovascular traits with clear external manifestations

Purpose The purpose of this study is to use a genotype-first approach to explore highly penetrant, autosomal dominant cardiovascular diseases with external features, the RASopathies and Marfan syndrome (MFS), using biobank data. Methods This study uses exome sequencing and corresponding phenotypic data from Mount Sinai's BioMe(n = 32,344) and the United Kingdom Biobank (UKBB;n = 49,960). Variant curation identified pathogenic/likely pathogenic (P/LP) variants in RASopathy genes andFBN1. Results Twenty-one subjects harbored P/LP RASopathy variants; three (14%) were diagnosed, and another 46% had >= 1 classic Noonan syndrome (NS) feature. Major NS features (short stature [9.5%p = 7e-5] and heart anomalies [19%,p < 1e-5]) were less frequent than expected. Prevalence of hypothyroidism/autoimmune disorders was enriched compared with biobank populations (p = 0.007). For subjects withFBN1P/LP variants, 14/41 (34%) had a MFS diagnosis or highly suggestive features. Five of 15 participants (33%) with echocardiographic data had aortic dilation, fewer than expected (p = 8e-6). Ectopia lentis affected only 15% (p < 1e-5). Conclusions Substantial fractions of individuals harboring P/LP variants with partial or full phenotypic matches to a RASopathy or MFS remain undiagnosed, some not meeting diagnostic criteria. Routine population genotyping would enable multidisciplinary care and avoid life-threatening events.

Jaar van publicatie:2021

Toegankelijkheid:Closed