Mol Genet Genomic Med. 2026 Jul;14(7):e70268. doi: 10.1002/mgg3.70268.
ABSTRACT
BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common hereditary cardiac disorder characterized by left ventricular hypertrophy, outflow tract obstruction, arrhythmias, and increased risk of sudden cardiac death.
METHODS: Clinical phenotypes and family histories were collected from affected individuals. Whole-exome sequencing (WES) followed by Sanger sequencing identified and validated genetic variants. In silico tools predicted splicing effects, with aberrant splicing confirmed by minigene assays.
RESULTS: The proband, a 33-year-old male with asymmetric obstructive HCM, exhibited characteristic electrocardiographic, echocardiographic, cardiac MRI, and histopathological findings. WES revealed MYBPC3 c.787G>A and MYH6 c.804G>C (p.Leu268=) variants. Segregation analysis showed that only the synonymous MYH6 variant co-segregated with HCM in affected family members. This variant was absent from public databases (gnomAD and ClinVar) and the literature as of December 15, 2025. Although three in silico tools predicted negligible splicing impact, minigene assays in HEK293T and HeLa cells revealed partial exon 10 skipping, resulting in an in-frame deletion (p.Leu268_Asp300del) in approximately 6.8% and 4.7% of transcripts, respectively.
CONCLUSION: The synonymous MYH6 c.804G>C variant promotes exon skipping and is associated with HCM. This study provides functional evidence supporting its potential pathogenicity and underscores the value of experimental validation in genetic diagnosis. These findings highlight the limitations of computational predictions and emphasize the importance of functional assays for evaluating synonymous variants in sarcomeric genes.
PMID:42418507 | DOI:10.1002/mgg3.70268