A Novel Truncating Variant in MYBPC3 Causes Hypertrophic Cardiomyopathy

Background Familial hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease. Related mutations contributing to hypercontractility and poor relaxation in HCM have been incompletely understood. The purpose of this study was to explore and verify a novel variant in cardiac myosin-binding protein C3 (MYBPC3) in a HCM family. Methods Clinical information was collected and cardiac evaluation was performed in the pedigree. Second-generation sequencing technology was used to investigate the proband and his family. Computational prediction of mutation effects at genomic level and 3D visualization of the mutated protein were achieved by in silico analysis. Results Typical interventricular septal thickening was detected in all the four HCM patients. A c.1042\_1043insCGGCA mutation of MYBPC3 was verified in the proband and family members. Mild phenotype associated with delayed onset and relative favorable prognosis were observed in the pedigree. In silico analysis of the mutation revealed that c.1042\_1043insCGGCA led to an early termination of MYBPC protein synthesis at C2 domain, losing the domains that are essential for myosin-and titin-binding. Conclusion The novel c.1042_1043insCGGCA mutation of MYBPC3 was a genetic basis for HCM. Our gene sequence based computational analysis predicted the pathogenicity of the mutation by correlating MYBPC3 genotypes with clinical phenotypes. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Yes ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang University. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All relevant data are within the manuscript and its Supporting Information files.