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.

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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.

References

  1. 1.

    Stessman HA, Bernier R, Eichler EE. A genotype-first approach to defining the subtypes of a complex disease. Cell. 2014;156:872–877.

    CAS  Article  Google Scholar 

  2. 2.

    Alver M, et al. Recall by genotype and cascade screening for familial hypercholesterolemia in a population-based biobank from Estonia. Genet Med. 2019;21:1173–1180.

    CAS  Article  Google Scholar 

  3. 3.

    Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lancet. 2013;381:333–342.

    CAS  Article  Google Scholar 

  4. 4.

    Pyeritz RE. Recent progress in understanding the natural and clinical histories of the Marfan syndrome. Trends Cardiovasc Med. 2016;26:423–428.

    Article  Google Scholar 

  5. 5.

    Aoki Y, Niihori T, Inoue S-i, Matsubara Y. Recent advances in RASopathies. J Hum Genet. 2016;61:33–39.

    CAS  Article  Google Scholar 

  6. 6.

    Tartaglia M, Gelb BD, Zenker M. Noonan syndrome and clinically related disorders. Best Pract Res Clin Endocrinol Metab. 2011;25:161–179.

    CAS  Article  Google Scholar 

  7. 7.

    Von Kodolitsch Y, Raghunath M, Nienaber C. Marfan syndrome: prevalence and natural course of cardiovascular manifestations. Z Kardiol. 1998;87:150.

    Google Scholar 

  8. 8.

    Thorvaldsdóttir H, Robinson JT, Mesirov JP. Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration. Brief Bioinform. 2013;14:178–192.

    Article  Google Scholar 

  9. 9.

    Wildeman M, Van Ophuizen E, Den Dunnen JT, Taschner PE. Improving sequence variant descriptions in mutation databases and literature using the Mutalyzer sequence variation nomenclature checker. Hum Mutat. 2008;29:6–13.

    CAS  Article  Google Scholar 

  10. 10.

    Freeman PJ, Hart RK, Gretton LJ, Brookes AJ, Dalgleish R. VariantValidator: accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat. 2018;39:61–68.

    Article  Google Scholar 

  11. 11.

    Gelb BD, et al. ClinGen’s RASopathy Expert Panel consensus methods for variant interpretation. Genet Med. 2018;20:1334–1345.

    Article  Google Scholar 

  12. 12.

    Baudhuin LM, Kluge ML, Kotzer KE, Lagerstedt SA. Variability in gene-based knowledge impacts variant classification: an analysis of FBN1 missense variants in ClinVar. European J Hum Genet. 2019;27:1550–1560.

    CAS  Article  Google Scholar 

  13. 13.

    Muiño-Mosquera L, et al. Tailoring the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Guidelines for the Interpretation of Sequenced Variants in the FBN1 Gene for Marfan Syndrome: proposal for a disease-and gene-specific guideline. Circ Genom Precis Med . 2018;11:e002039.

    Article  Google Scholar 

  14. 14.

    Loeys BL, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010;47:476–485.

    CAS  Article  Google Scholar 

  15. 15.

    Desmet F-O, et al. Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res. 2009;37:e67–e67.

    Article  Google Scholar 

  16. 16.

    Reese MG, Eeckman FH, Kulp D, Haussler D. Improved splice site detection in Genie. J Comput Biol. 1997;4:311–323.

    CAS  Article  Google Scholar 

  17. 17.

    Yeo G, Burge CB. Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J Comput Biol. 2004;11:377–394.

    CAS  Article  Google Scholar 

  18. 18.

    Kopanos C, et al. VarSome: the human genomic variant search engine. Bioinformatics. 2019;35:1978.

    CAS  Article  Google Scholar 

  19. 19.

    Devereux RB, et al. Normal limits in relation to age, body size and gender of two-dimensional echocardiographic aortic root dimensions in persons≥ 15 years of age. Am J Cardiol. 2012;110:1189–1194.

    Article  Google Scholar 

  20. 20.

    Santos FP, et al. Prognostic impact of RAS-pathway mutations in patients with myelofibrosis. Leukemia. 2020;34:799–810.

    CAS  Article  Google Scholar 

  21. 21.

    Lo F-S, et al. Noonan syndrome caused by germline KRAS mutation in Taiwan: report of two patients and a review of the literature.Eur J Pediatr. 2009;168:919.

  22. 22.

    Van Der Burgt I, et al. Clinical and molecular studies in a large Dutch family with Noonan syndrome. Am J Med Genet. 1994;53:187–191.

    Article  Google Scholar 

  23. 23.

    Prendiville TW, et al. Cardiovascular disease in Noonan syndrome. Arch Dis Child. 2014;99:629–634.

    Article  Google Scholar 

  24. 24.

    Gripp KW, et al. Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis. Am J Med Genet A. 2013;161:2420–2430.

    CAS  PubMed Central  Google Scholar 

  25. 25.

    Rybczynski M, et al. Frequency and age-related course of mitral valve dysfunction in the Marfan syndrome. Am J Cardiol. 2010;106:1048–1053.

    Article  Google Scholar 

  26. 26.

    Lacro RV, et al. Characteristics of children and young adults with Marfan syndrome and aortic root dilation in a randomized trial comparing atenolol and losartan therapy. Am Heart J. 2013;165:828–35. e3.

    CAS  Article  Google Scholar 

  27. 27.

    Nahum Y, Spierer A. Ocular features of Marfan syndrome: diagnosis and management. Isr Med Assoc J. 2008;10:179.

    PubMed  Google Scholar 

  28. 28.

    Haggerty CM, et al. Genomics-first evaluation of heart disease associated with titin-truncating variants. Circulation. 2019;140:42–54.

    CAS  Article  Google Scholar 

  29. 29.

    Haggerty CM, et al. Electronic health record phenotype in subjects with genetic variants associated with arrhythmogenic right ventricular cardiomyopathy: a study of 30,716 subjects with exome sequencing. Genet Med. 2017;19:1245–1252.

    Article  Google Scholar 

  30. 30.

    Park J. et al. A genome-first approach to aggregating rare genetic variants in LMNA for association with electronic health record phenotypes. Genet Med. 2020;22:102–111.

    CAS  Article  Google Scholar 

  31. 31.

    Noonan JA. Associated noncardiac malformations in children with congenital heart disease. J Pediatr. 1963;63:468–470.

    Google Scholar 

  32. 32.

    Noonan JA, Raaijmakers R, Hall B. Adult height in Noonan syndrome. Am J Med Genet A. 2003;123:68–71.

    Article  Google Scholar 

  33. 33.

    Alpendurada F, et al. Evidence for Marfan cardiomyopathy. Eur J Heart Fail. 2010;12:1085–1091.

    Article  Google Scholar 

  34. 34.

    Sharland M, Burch M, McKenna W, Paton M. A clinical study of Noonan syndrome. Arch Dis Child. 1992;67:178–183.

    CAS  Article  Google Scholar 

  35. 35.

    Lee MJ, et al. Hashimoto thyroiditis with an unusual presentation of cardiac tamponade in Noonan syndrome. Korean J Pediatr. 2016;59:S112.

    Article  Google Scholar 

  36. 36.

    Amoroso A, et al. The unusual association of three autoimmune diseases in a patient with Noonan syndrome. J Adolesc Health. 2003;32:94–97.

    Article  Google Scholar 

  37. 37.

    Svensson J, Carlsson A, Ericsson UB, Westphal O, Ivarsson SA. Noonan’s syndrome and autoimmune diseases. J Pediatr Endocrinol Metab. 2003;16:217–218.

    CAS  Article  Google Scholar 

  38. 38.

    Uehara T, Hosogaya N, Matsuo N, Kosaki K. Systemic lupus erythematosus in a patient with Noonan syndrome‐like disorder with loose anagen hair 1: more than a chance association. Am J Med Genet A. 2018;176:1662–1666.

    Article  Google Scholar 

  39. 39.

    Bader-Meunier B, et al. Are RASopathies new monogenic predisposing conditions to the development of systemic lupus erythematosus? Case report and systematic review of the literature. Semin Arthritis Rheum. 2013;43:217–219.

    Article  Google Scholar 

  40. 40.

    Quaio CR, et al. Autoimmune disease and multiple autoantibodies in 42 patients with RASopathies. Am J Med Genet A. 2012;158:1077–1082.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

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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Disclosure

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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Keywords

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

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