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

Abstract

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.

Keywords: Mendelian disorders; cardiovascular system; exome sequencing; genotype–phenotype correlations; precision medicine.

Figure 1:. Height of participants with P/LP variants.

A) RASopathy genes. Diamonds, individuals diagnosed with Noonan syndrome; circles, undiagnosed individuals. As indicated in the key, colors correspond to the genes harboring the P/LP variants. B) FBN1. As indicated in the key, colors correspond to the clinical status of the individuals. Significant features include ≥ 2 of the following: aortic dilation, height z-score >2, ectopia lentis, retinal detachment, congenital skeletal abnormalities, family history of MFS-phenotype, nonrheumatic mitral valve abnormalities

Figure 2:. Phenotypes of individuals with underlying pathogenic/likely pathogenic RASopathy variation by diagnosis status.

The major and minor signs for diagnosing are as per van der Burgt.

Figure 3:. Phenotypes of individuals with underlying pathogenic/likely pathogenic FBN1 variation by diagnosis status.

The diagnostic features are as per the revised Ghent criteria. Abbreviation: MSK, musculoskeletal.