Analysis of HCM in an understudied population reveals a new mechanism of pathogenicity

Hypertrophic Cardiomyopathy (HCM) is an inherited disease characterized by genetic and phenotypic heterogeneity. MYH7 represents one of the main sarcomere-encoding genes associated with HCM. Missense variants in this gene cause HCM through gain-of-function actions, whereby variants produce an abnormal activated protein which incorporates into the sarcomere as a ‘poison peptide’. Here we report a frameshift variant in MYH7 , c.5769delG, that is associated with HCM in an Egyptian cohort (3.3%) compared with ethnically-matched controls. This variant is absent from previously published large-scale Caucasian HCM cohorts. We further demonstrate strong evidence of co-segregation of c.5769delG with HCM in a large family (LOD score: 3.01). The predicted sequence of the variant MYH7 transcript shows that the frameshift results in a premature termination codon (PTC) downstream of the last exon-exon junction of the gene that is expected to escape nonsense-mediated decay (NMD). RNA sequencing of myocardial tissue obtained from a patient with the variant during surgical myectomy confirmed the expression of the variant MYH7 transcript. Our analysis reveals a new mechanism of pathogenicity in the understudied Egyptian population whereby distal PTC in MYH7 may lead to the expression of an abnormal protein. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study is part of the Egyptian Collaborative Cardiac Genomics (ECCO-GEN) Project. It was supported by the Science and Technology Development Fund (STDF) government grant (Egypt), the Wellcome Trust(107469/Z/15/Z; 200990/A/16/Z), the Medical Research Council (UK), the NIHR Biomedical Research Unit in Cardiovascular Disease at Royal Brompton & Harefield NHS Foundation Trust and Imperial College London, the NIHR Imperial College Biomedical Research Centre a Health Innovation Challenge Fund award from the Wellcome Trust and Department of Health, UK (HICF-R6-373). M. A. and S.H. are funded by Al Alfi Foundation to support their Ph.D. degrees at Imperial College London and American University in Cairo, respectively. Y.A. is supported by Foundation Leducq (11 CVD-01). N.W. is supported by a Rosetrees and Stoneygate Imperial College Research Fellowship. R.W. is supported by an Amsterdam Cardiovascular Science Fellowship. ### Author Declarations All relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript. Yes All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Raw data from this study will be submitted to the European Genome-phenome Archive (EGA).