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<p><i>MYBPC3</i> pathogenic variants are the most common cause of hypertrophic cardiomyopathy (HCM) and are associated with significant phenotypic heterogeneity. Despite their pathogenic potential, <i>MYBPC3</i> founder variants persist within specific populations. This study investigates the <i>MYBPC3</i> c.2309-2 A &gt; 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 <i>MYBPC3</i> 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 <i>MYBPC3</i> variants, and among these, 11.6% carried the c.2309-2 A &gt; 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 &gt; 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 <i>MYBPC3</i> expression consistent with haploinsufficiency. Comparative analysis with other <i>MYBPC3</i> founder variants highlighted differences in phenotypic expression, particularly in left ventricular wall thickness and clinical outcomes. This study establishes c.2309-2 A &gt; G as an Italian <i>MYBPC3</i> 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 <i>MYBPC3</i> c.2309-2 A &gt; G carriers.</p><p></p>

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MYBPC3 c.2309-2A>G: exploring a founder variant in Italian hypertrophic cardiomyopathy patients

  • 期刊论文

  • 发表日期：

    2025年5月31日

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  • Marco Fabiani,
  • Caterina Micolonghi,
  • Silvia Caroselli,
  • Camilla Savio,
  • Simona Petrucci,
  • Giacomo Tini,
  • Beatrice Musumeci,
  • Erika Pagannone,
  • Ludovica De Fazio,
  • Aldo Germani,
  • Vincenzo Visco,
  • Antonio Pizzuti,
  • Liana Veneziano,
  • Enrica Marchionni,
  • Ruggiero Mango,
  • Laura Pezzoli,
  • Irene Bottillo,
  • Camilla Lucca,
  • Agnese Scatigno,
  • Lucrezia Goisis,
  • Francesca Cappuccini,
  • Maria Pia Ciccone,
  • Adelaide Ballerini,
  • Alessia Gozzini,
  • Valerio Onofri,
  • Carlotta Pia Cristalli,
  • Andrea Latini,
  • Daniela D’Angelantonio,
  • Francesca Gualandi,
  • Giada Tortora,
  • Monia Magliozzi,
  • Antonio Novelli,
  • Cesare Rossi,
  • Paola Grammatico,
  • Federica Sangiuolo,
  • Francesca Girolami,
  • Maria Iascone,
  • Iacopo Olivotto,
  • Camillo Autore,
  • Speranza Rubattu,
  • Maria Piane

摘要

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.