The genetic spectrum of hypertrophic cardiomyopathy in an irish cohort

Abstract Background Hypertrophic cardiomyopathy (HCM) has long been described as the archetypal monogenic cardiac disease. It fulfils criteria for Mendelian inheritance and painstaking early co-segregation studies by Seidman et al in 1990 lead to discovery that mutations MYH7 cause HCM. From here, genetic architecture of HCM gradually assembled thousands individual discovered. The complexity genetics continues evolve include gene-negative cohort those carrying multiple mutations. We sought describe spectrum an Irish population. Methods A retrospective examination proband database a specialist clinic was undertaken select all patients with gene-positive Their clinical data imaging reviewed. Mutations classified American College Medical Genetics Class 4 5 were considered pathogenic. Variants uncertain significance (VUS) candidate genes also recorded, though not clinically actionable. Results results testing 254 94% (n=238) had single pathogenic gene mutation. 5% (n=13) digenic remaining 1% (n=3) oligogenic MYBPC3 most commonly involved 116 (45.6%) variant. p. Arg502Trp missense mutation is common observed within founder effect England. found 51 (20%). Troponin 20 (6.8%). Although formally VUS, there overrepresentation FHOD3 19 (7.4%) 41 (16%) PRKAG2, LAMP2 mitochondrial collectively. Discussion This similar profile sarcomeric published European registry data. There phenocopy/metabolic conditions such PRKAG2-associated cardiomyopathy. represents genetically homogenous small population Ireland but includes one largest Danon disease cohorts Europe. hypertrophic complex concept over-simplification. significant phenotypic variability due gene-gene effects gene-dose effects, well elusive epigenetic modifier effects. Our understanding complexities evolve. Funding Acknowledgement Type funding sources: Public grant(s) – National budget only. Main source(s): Mater Foundation