Key result
Novel MYBPC3 insertion mutation links to hypertrophic cardiomyopathy via haploinsufficiency and reduced protein expression.
Why the study?
Mutations contributing to hypercontractility and poor relaxation in familial hypertrophic cardiomyopathy are not completely understood, prompting investigation of a novel MYBPC3 variant in an affected family.
Observational (n=4)
No
p-value: p=<0.05
The identification of a novel pathogenic MYBPC3 frameshift mutation (c.1042_1043insCGGCA) causing haploinsufficiency expands the genetic spectrum of hypertrophic cardiomyopathy and highlights the utility of genetic screening in family risk stratification.
Supports targeted screening in this pedigree; extends MYBPC3 mutation spectrum but remains hypothesis-generating.
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. PURPOSE: 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 in the pedigree. 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. The cardiac expression levels of MYBPC3 mRNA and cMyBP-C protein were assessed using RT-qPCR and Western blot analysis, respectively. RESULTS: Typical interventricular septal thickening was detected in all four HCM patients without left ventricular outflow tract obstruction. The c.1042_1043insCGGCA mutation in MYBPC3 was verified in the proband and family members. In silico analysis of the mutation revealed that c.1042_1043insCGGCA led to a shift in the sequence of nucleotides, creating a premature stop codon at the new reading frame. RT-qPCR analysis of MYBPC3 mRNA revealed a marked reduction in HCM heart compared to the normal controls (P < 0.05). Consistently, Western blot analysis showed significantly reduced expression of cMyBP-C in the pedigree in comparison with the controls (P < 0.05). CONCLUSION: The novel c.1042_1043insCGGCA MYBPC3 mutation is a genetic basis for HCM due to c-MyBP-C haploinsufficiency.
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Zhang et al. (2025) conducted an observational in Hypertrophic cardiomyopathy (n=4). MYBPC3 c.1042_1043insCGGCA mutation vs. Normal controls was evaluated on Cardiac expression levels of MYBPC3 mRNA and cMyBP-C protein (p=<0.05). The novel c.1042_1043insCGGCA mutation in MYBPC3 causes hypertrophic cardiomyopathy through haploinsufficiency, demonstrating significantly reduced MYBPC3 mRNA and cMyBP-C protein expression compared to controls (P < 0.05).
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