title: Prevalence of sequence variants in the RAS-mitogen activated protein kinase signaling pathway in pre-adolescent children with hypertrophic cardiomyopathy.
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.
  
  
  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.
authors.affiliation: Institute of Child Health, University College, London, United Kingdom.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Kaski
authors.forename: Petros
authors.initials: P
authors.lastname: Syrris
authors.forename: Adam
authors.initials: A
authors.lastname: Shaw
authors.forename: Krisztina Zuborne
authors.initials: KZ
authors.lastname: Alapi
authors.forename: Viviana
authors.initials: V
authors.lastname: Cordeddu
authors.forename: Maria Teresa Tome
authors.initials: MT
authors.lastname: Esteban
authors.forename: Sharon
authors.initials: S
authors.lastname: Jenkins
authors.forename: Michael
authors.initials: M
authors.lastname: Ashworth
authors.forename: Peter
authors.initials: P
authors.lastname: Hammond
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.forename: William J
authors.initials: WJ
authors.lastname: McKenna
authors.forename: Perry M
authors.initials: PM
authors.lastname: Elliott
mesh_terms: D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D010375:Pedigree; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins