Abstract Body (Do not enter title and authors here): 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.