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 and FBN1. 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 to biobank populations (p = 0.007). For subjects with FBN1 P/LP variants, 14/41 (34%) had a MFS diagnosis or highly suggestive features. 5/15 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 multi-disciplinary care and avoid life-threatening events.