The Novel Frameshift Variant of the MYBPC3 Gene Associated with Hypertrophic Cardiomyopathy Significantly Decreases the Level of This Gene Transcript in the Myocardium

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease with a prevalence of 1 : 200–1 : 500 in the general population. Most HCM-linked pathogenic (or likely pathogenic) variants are located in eight genes encoding proteins of sarcomere, the main contractile unit of cardiomyocytes, primarily in MYBPC3; MYBPC3 variants are usually associated with a relatively benign clinical course of the disease. Here, we describe a novel frameshift heterozygous variant NM_000256.3:c.2781_2782insCACA of the MYBPC3 gene, which causes familial HCM. The proband had a progressive heart failure despite the surgical removal of left ventricular tract obstruction. Evaluation of levels of transcripts produced from the mutant allele and wild-type allele of the MYBPC3 gene in proband myocardial tissue and comparison of their total levels with those in the control samples from patients without HCM showed a significant allele-specific reduction of mutant transcript levels. Our results expand the spectrum of known genetic variants with a proven role in the development of HCM.