Prevalence of sequence variants in the RAS-mitogen activated protein kinase signaling pathway in pre-adolescent children with hypertrophic cardiomyopathy

Juan Pablo Kaski, Petros Syrris, Adam Shaw, Krisztina Zuborne Alapi, Viviana Cordeddu, Maria Teresa Tome Esteban, Sharon Jenkins, Michael Ashworth, Peter Hammond, Marco Tartaglia, William J. McKenna, Perry M. Elliott

Research output: Contribution to journalArticle

Abstract

Background- Most cases of apparently idiopathic hypertrophic cardiomyopathy (HCM) in children are caused by mutations in cardiac sarcomere protein genes. HCM also commonly occurs as an associated feature in some patients with disorders caused by mutations in genes encoding components of the RAS-mitogen activated protein kinase (MAPK) signaling pathway. Although diagnosis of these disorders is based on typical phenotypic features, the dysmorphic manifestations can be subtle and therefore overlooked. The aim of this study was to determine the prevalence of mutations in RAS-MAPK genes in preadolescent children with idiopathic HCM. Methods and Results- Seventy-eight patients diagnosed with apparently nonsyndromic HCM aged ≤13 years underwent clinical and genetic evaluation. The entire protein coding sequence of 9 genes implicated in Noonan syndrome and related conditions (PTPN11, SOS1, HRAS, KRAS, NRAS, BRAF, RAF1, MAP2K1, and MAP2K2), together with CBL (exons 8 and 9) and SHOC2 (4A>G), were screened for mutations. Five probands (6.4%) carried novel sequence variants in SOS1 (2 individuals), BRAF, MAP2K1, and MAP2K2. Structural and molecular data suggest that these variants may have functional significance. Nine cardiac sarcomere protein genes were screened also; 2 individuals also had mutations in MYBPC. Conclusions- This study reports novel and potentially pathogenic sequence variants in genes of the RAS-MAPK pathway, suggesting that genetic lesions promoting signaling dysregulation through RAS contribute to disease pathogenesis or progression in children with HCM.

Original languageEnglish
Pages (from-to)317-326
Number of pages10
JournalCirculation: Cardiovascular Genetics
Volume5
Issue number3
DOIs
Publication statusPublished - Jun 2012

Keywords

  • Cardiomyopathy
  • Genetics
  • Rasopathy
  • Signal transduction
  • Syndrome

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)
  • Genetics

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    Kaski, J. P., Syrris, P., Shaw, A., Alapi, K. Z., Cordeddu, V., Esteban, M. T. T., Jenkins, S., Ashworth, M., Hammond, P., Tartaglia, M., McKenna, W. J., & Elliott, P. M. (2012). Prevalence of sequence variants in the RAS-mitogen activated protein kinase signaling pathway in pre-adolescent children with hypertrophic cardiomyopathy. Circulation: Cardiovascular Genetics, 5(3), 317-326. https://doi.org/10.1161/CIRCGENETICS.111.960468