Hypertrophic cardiomyopathy caused by MYBPC3 mutations represents a major genetic contributor to cardiomyopathy. Presented at the European Society of Cardiology (ESC) Congress 2025, data from eight regional cardiology centers examined 44 patients carrying c.1458-1G>A and 18 with c.3331-1G>A variants.

Haplotype analysis suggested both variants originated from a common ancestor, consistent with a founder effect, which explains their high recurrence. Functional studies confirmed significant splicing alterations, including exon skipping and activation of cryptic splice sites. Despite later diagnosis in variant carriers, comparison with 179 patients harboring other pathogenic or likely pathogenic sarcomeric mutations revealed no significant differences in clinical presentation, echocardiographic parameters, or incidence of major cardiac events. Even when compared to 119 patients with MYBPC3 mutations, outcomes and phenotypic expression remained comparable.

These findings highlight that recurrent founder-effect MYBPC3 variants are associated with an indolent clinical course but similar prognosis. Their identification and characterization are important for population-level genetic screening and may inform future gene therapy interventions.