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



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.


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.


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).


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.

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Fig. 1: Height of participants with pathogenic/likely pathogenic (P/LP) variants.
Fig. 2: Phenotypes of individuals with underlying pathogenic/likely pathogenic RASopathy variation by diagnosis status.
Fig. 3: Phenotypes of individuals with underlying pathogenic/likely pathogenic FBN1 variation by diagnosis status.


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We acknowledge the participants enrolled in BioMe and UKBB, without whom this research would not be possible. We also acknowledge the ongoing work of the Mount Sinai’s Charles Bronfman Institute for Personalized Medicine for ongoing curation of BioMe. This work was supported in part by United States Public Health Service (USPHS) grant to R.D. (GM124836 and HL139865), B.D.G. (HL135742), and A.R.K. (HL140083) and grants from Italian Association for Cancer Research (IG21614), European Joint Programme on Rare Diseases (NSEuroNet) to M.T. J.D.B is supported as senior clinical researcher by the Research Foundation Flanders and holds a Grant for Medical Research from the Baillet Latour Funds. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award numbers S10OD018522 and S10OD026880. This work was also supported in part through the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland. This research has been conducted using the UK Biobank Resource under application number 16218.

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Correspondence to Bruce D. Gelb MD.

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B.D.G. and M.T. receive royalties for genetic testing of the RASopathies from Correlegan, GeneDx, LabCorp, and Prevention Genetics. D.R.S. performs contract telegenetics services for Genome Medical, Inc., in accordance with relevant National Cancer Institute ethics policies. The other authors declare no conflicts of interest.

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Wenger, B.M., Patel, N., Lui, M. et al. A genotype-first approach to exploring Mendelian cardiovascular traits with clear external manifestations. Genet Med (2020). https://doi.org/10.1038/s41436-020-00973-2

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  • exome sequencing
  • Mendelian disorders
  • cardiovascular system
  • genotype–phenotype correlations
  • precision medicine