Key result
Specific MYBPC3 founder variants are linked to delayed onset and lower sudden death risk.
Why the study?
Founder mutations in MYBPC3 may contribute substantially to the genetic burden of HCM, prompting investigation of two recurrent canonical splice-site variants identified in patients from Northern Italy.
Do the MYBPC3 c.1458-1G>A and c.3331-1G>A founder variants result in a different clinical phenotype and outcome compared to other sarcomeric variants in patients with hypertrophic cardiomyopathy?
Observational (n=220)
Yes
Do the MYBPC3 c.1458-1G>A and c.3331-1G>A founder variants result in a different clinical phenotype and outcome compared to other sarcomeric variants in patients with hypertrophic cardiomyopathy?
The identification of these two locally prevalent MYBPC3 founder mutations in Northern Italy, which are associated with a delayed and milder HCM phenotype, improves molecular diagnosis and family screening.
Supports milder HCM phenotypes with these founder variants; leaves open prospective validation for variant-specific risk stratification.
Background: Founder mutations in MYBPC3 may contribute substantially to the genetic burden of hypertrophic cardiomyopathy (HCM) and provide important insights into genotype–phenotype correlations and population-specific disease mechanisms. In this study, we investigated two recurrent canonical splice-site variants, MYBPC3 c.1458-1G>A and c.3331-1G>A, identified in patients with HCM from the Emilia-Romagna region of Northern Italy. Methods: Ninety-one unrelated patients with HCM carrying either MYBPC3c.1458-1G>A or c.3331-1G>A were analyzed. Haplotype reconstruction was performed to assess a possible founder effect and estimate the approximate age of the shared ancestral allele. Functional characterization was carried out by RNA sequencing of myocardial tissue to evaluate the impact of the variants on splicing. Clinical and phenotypic data were compared with those of carriers of other truncating MYBPC3 variants or pathogenic variants in other sarcomeric genes. Results: Both variants, classified as pathogenic according to ACMG criteria, shared a conserved variant-specific core haplotype. Founder age was estimated at approximately 10.5 generations (~262 years), consistent with a regional founder effect. RNA sequencing demonstrated aberrant splicing for both variants, resulting in premature termination codons and presumably subsequent nonsense-mediated mRNA decay. Clinically, carriers showed delayed disease onset, with a mean onset in the fifth decade of life, and a comparatively milder phenotype, including a lower incidence of sudden cardiac death, than patients carrying other truncating MYBPC3 variants or pathogenic variants in other sarcomeric genes. Both variants exhibited partial penetrance (approximately 63–67%) and age-dependent variable expressivity. Conclusions:MYBPC3 c.1458-1G>A and c.3331-1G>A represent novel founder alleles associated with HCM in Northern Italy. Identification of these locally prevalent variants improves molecular diagnosis, family screening, and supports the development of variant-targeted therapeutic approaches.
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Cristalli et al. (2026) conducted an observational in Hypertrophic Cardiomyopathy (n=220). MYBPC3 c.1458-1G>A and c.3331-1G>A variants vs. Other truncating MYBPC3 variants or pathogenic variants in other sarcomeric genes was evaluated on Age at diagnosis and family history of sudden cardiac death. The MYBPC3 c.1458-1G>A and c.3331-1G>A founder variants were associated with delayed disease onset and a milder phenotype, including a lower incidence of familial sudden cardiac death, compared to other truncating MYBPC3 variants.
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