Key result
Novel MYBPC3 nonsense variant links to variable HCM phenotypes across affected family members.
Why the study?
The relationship between novel pathogenic MYBPC3 gene variants and clinical phenotypes in hypertrophic cardiomyopathy remains to be elucidated.
Observational
A novel MYBPC3 nonsense variant (c.2731G > T) was identified as the cause of hypertrophic cardiomyopathy in a family, highlighting the utility of whole-exome sequencing for early screening and diagnosis.
Expands MYBPC3 variant spectrum in HCM; hypothesis-generating without changing screening practice.
OBJECTIVES: This study aims to investigate the pathogenic gene variant in a family with hypertrophic cardiomyopathy by using whole-exome sequencing and to explore the relationship between the gene variant and clinical phenotype. METHODS: Peripheral blood was collected from a family with hypertrophic cardiomyopathy, and deoxyribonucleic acid was extracted. The possible pathogenic genes were detected by whole-exome sequencing, and the variant was verified by Sanger sequencing. Functional change in the variant was predicted by bioinformatics software. Clinical data of the family members are analysed simultaneously. RESULTS: The proband carries a novel heterozygous nonsense variant of MYBPC3:c.2731G > T (p.E911X). The analysis of amino acid conservation suggests that the variation is highly conserved. The three-dimensional protein structure shows that the variant in MYBPC3 results in the incompleteness of the fibronectintype-III2 (p872-967) domain and deletion of Ig-like C2-type 6 (p971-1065) and fibronectin type-III 3 and Ig-like C2-type 7 (p1181-1274) domains, in which p1253-1268 is predicted to have a transmembrane helix structure. Clinical data indicate that the phenotypes of variant carriers with hypertrophic cardiomyopathy are diverse, suggesting the functional damages to the protein of MYBPC3. CONCLUSION: The phenotypes of variant carriers with hypertrophic cardiomyopathy caused by the novel variant in MYBPC3: c.2731G > T (p.E911X) exhibit variable severity and clinical manifestations. Whole-exome sequencing can be used to comprehensive screen hypertrophic cardiomyopathy genes and provide a strong basis for early screening and accurate diagnosis and treatment of hypertrophic cardiomyopathy in children.
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A 2021 study conducted an observational in Hypertrophic cardiomyopathy. MYBPC3:c.2731G > T (p.E911X) variant was evaluated on Clinical phenotype and functional changes associated with the variant. A novel heterozygous nonsense variant of MYBPC3:c.2731G > T (p.E911X) was identified in a family with hypertrophic cardiomyopathy, resulting in diverse clinical phenotypes and variable severity.
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