Abstract 4368316: A Novel Variant in <i>MYBPC</i> 3 Causes Hypertrophic Cardiomyopathy by Haploinsufficiency

Background: Familial hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease (CVD ) . Related mutations contributing to hypercontractility and poor relaxation in HCM are not completely understood. This study aimed to explore and verify a novel variant of cardiac myosin-binding protein C (cMyBP-C, encoded by MYBPC3 ) in an HCM family. Methods: Clinical information and cardiac parameters were collected for the patients. Genomic DNA was extracted from peripheral blood and second-generation sequencing technology was used to investigate the proband and his family members. Subsequent sequence analysis was performed with DNAMAN software. Cardiac expression level of cMyBP-C was assessed using Western blot analysis. Results: Typical interventricular septal thickening was detected in all four HCM patients without left ventricular outflow tract obstruction. The M348fs mutation in MYBPC3 was verified in proband and family members. A mild phenotype associated with delayed onset but a high risk of sudden cardiac death was observed in the family. In silico analysis of the mutation revealed that M348fs led to a shift in the sequence of nucleotides, creating a premature stop codon at the new reading frame. Consistently, Western blot analysis showed significantly reduced expression of cMyBP-C in HCM hearts compared to the controls. Conclusions: The novel M348fs MYBPC3 mutation is a genetic basis for HCM due to c-MyBP-C haploinsufficiency. Periodic assessment and genetic consultation are necessary since the risk of sudden cardiac death remains high in patients with mild phenotypes.