Deep-intronic MYBPC3 variant identified as pathogenic cause of HCM

Researchers used massively parallel sequencing to identify a previously unreported deep-intronic variant, c.2308+227G>A, in genotype-negative hypertrophic cardiomyopathy patients from Salamanca, Spain, despite splice prediction tools scoring it as likely benign. Across 35 probands and 46 relatives (81 confirmed carriers), 69% met HCM diagnostic criteria, with cosegregation analysis, splicing assays in blood and cardiac tissue, and haplotype reconstruction supporting pathogenicity via amplification of pre-existing cryptic splice sites rather than creation of new ones; the study reports no significant differences in heart failure, arrhythmic events, atrial fibrillation, or mortality compared with carriers of other pathogenic variants. The authors state that elusive splice-altering variants should be considered in HCM patients with unresolved genetic testing results.

Most relevant for: Patients with hypertrophic cardiomyopathy who have tested genotype-negative on standard DNA testing and their relatives undergoing family cascade screening.

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