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

Brittany M Wenger, Nihir Patel, Madeline Lui, Arden Moscati, Ron Do, Douglas R Stewart, Marco Tartaglia, Laura Muiño-Mosquera, Julie De Backer, Amy R Kontorovich, Bruce D Gelb

Research output: Contribution to journalArticlepeer-review


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 with biobank populations (p = 0.007). For subjects with FBN1 P/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.

Original languageEnglish
Pages (from-to)94-102
Number of pages9
JournalGenetics in Medicine
Issue number1
Publication statusPublished - Jan 2021


  • Fibrillin-1/genetics
  • Genotype
  • Humans
  • Marfan Syndrome/diagnosis
  • Mutation
  • Phenotype
  • United Kingdom/epidemiology


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