Abstract
MYBPC3 pathogenic variants are the most common cause of hypertrophic cardiomyopathy (HCM) and are associated with significant phenotypic heterogeneity. Despite their pathogenic potential, MYBPC3 founder variants persist within specific populations. This study investigates the MYBPC3 c.2309-2 A > G splice variant hypothesizing its founder origin in central Italy. The aim was to confirm the presence of a common haplotype, assess its molecular and clinical impact, and compare the phenotype with that of other MYBPC3 founder variants. Among the 5251 HCM patients recruited at eight Italian referral centers, 1108 probands (21.1%) were identified as carriers of pathogenic or likely pathogenic MYBPC3 variants, and among these, 11.6% carried the c.2309-2 A > G variant. Haplotype reconstruction using short tandem repeats and tag-SNPs revealed a unique 5.2 Mb haplotype segregating with the c.2309-2 A > G variant in all carriers. Age estimation suggested that the variant originated approximately 481 years ago, likely in the Lazio region with clustering in Rome. Clinically, carriers exhibited variable expressivity with age-and sex-dependent penetrance. Males showed earlier onset, higher penetrance and greater disease severity compared to females. RNA analysis showed the retention of both introns 23 and 24, and significantly reduced MYBPC3 expression consistent with haploinsufficiency. Comparative analysis with other MYBPC3 founder variants highlighted differences in phenotypic expression, particularly in left ventricular wall thickness and clinical outcomes. This study establishes c.2309-2 A > G as an Italian MYBPC3 founder mutation, enhancing the understanding of HCM genetics and regional founder effects. These findings emphasize the importance of targeted genetic screening and personalized management for MYBPC3 c.2309-2 A > G carriers.
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Data availability
The datasets generated and analyzed during the current study are included in the supplementary materials and are also available from the corresponding author upon request.
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Funding
This work was partially funded by Progetto PRIN 2022 (from the Italian Ministry of Instruction, University and Research, no. 2022E75TWB) to S.R. The research leading to these results has also received funding from the European Union-NextGenerationEU through the Italian Ministry of University and Research under PNRR–M4C2-I1.3 Project PE_00000019 “HEAL ITALIA”, CUP B53C22004000006 to S.R. The views and opinions expressed are those of the authors only and do not necessarily reflect those of the European Union or the European Commission. Neither the European Union nor the European Commission can be held responsible for them.
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MF and MP conceptualized and designed the study and wrote the original draft. MF, CM, CS, LV and MP performed haplotype analyses. VV, AP, and MP coordinated the study, with MP and SR providing writing review and editing. SC and CS provided methodology and software. CS, IB, MPC, and VO performed genetic analyses. AL, EM, and RM performed RT-PCR analyses, with EM and RM also providing samples and clinical data. CL, AS, LG, and FC performed RNAseq analyses and provided samples and clinical data, while MI coordinated participant recruitment and also coordinated RNAseq analyses. AGE carried out data curation and statistical analyses, and LV provided genomics expertise. CM, SP, LP, AB, AGO, GTI, BM, EP, LDF, and CPC provided samples collected clinical data. DD, FGU, GTO, MM, AN, CR, PG, FS, FGI, IO, and CA collected clinical data and coordinated the recruitment of study participants. European Union-NextGenerationEU.
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The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of A.O.U. Sant’Andrea (Ref 7310 Protocol number 0955/2023 29/11/2023) for studies involving humans. Informed consent was obtained from all subjects involved in the study.
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Fabiani, M., Micolonghi, C., Caroselli, S. et al. MYBPC3 c.2309-2A>G: exploring a founder variant in Italian hypertrophic cardiomyopathy patients. Eur J Hum Genet (2025). https://doi.org/10.1038/s41431-025-01873-2
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DOI: https://doi.org/10.1038/s41431-025-01873-2
