The genetic spectrum of hypertrophic cardiomyopathy in an irish cohort

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