Fabiani Marco, Micolonghi Caterina, Caroselli Silvia, Savio Camilla, Petrucci Simona, Tini Giacomo, Musumeci Beatrice, Pagannone Erika, De Fazio Ludovica, Germani Aldo, Visco Vincenzo, Pizzuti Antonio, Veneziano Liana, Marchionni Enrica, Mango Ruggiero, Pezzoli Laura, Bottillo Irene, Lucca Camilla, Scatigno Agnese, Goisis Lucrezia, Cappuccini Francesca, Ciccone Maria Pia, Ballerini Adelaide, Gozzini Alessia, Onofri Valerio, Cristalli Carlotta Pia, Latini Andrea, D'Angelantonio Daniela, Gualandi Francesca, Tortora Giada, Magliozzi Monia, Novelli Antonio, Rossi Cesare, Grammatico Paola, Sangiuolo Federica, Girolami Francesca, Iascone Maria, Olivotto Iacopo, Autore Camillo, Rubattu Speranza, Piane Maria
Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
Sant'Andrea University Hospital, Rome, Italy.
Eur J Hum Genet. 2025 May 31. doi: 10.1038/s41431-025-01873-2.
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.
MYBPC3致病变体是肥厚型心肌病（HCM）最常见的病因，且与显著的表型异质性相关。尽管具有致病潜力，但MYBPC3始祖变体仍在特定人群中存在。本研究调查了MYBPC3基因c.2309-2 A>G剪接变体，推测其起源于意大利中部的始祖变体。目的是确认常见单倍型的存在，评估其分子和临床影响，并将该表型与其他MYBPC3始祖变体的表型进行比较。在意大利八个转诊中心招募的5251例HCM患者中，1108例先证者（21.1%）被确定为致病或可能致病的MYBPC3变体携带者，其中11.6%携带c.2309-2 A>G变体。使用短串联重复序列和标签单核苷酸多态性进行单倍型重建，发现所有携带者中存在一个独特的5.2 Mb单倍型与c.2309-2 A>G变体共分离。年龄估计表明，该变体大约起源于481年前，可能在拉齐奥地区，在罗马聚集。临床上，携带者表现出可变的表达，具有年龄和性别依赖性外显率。与女性相比，男性发病更早、外显率更高且疾病严重程度更高。RNA分析显示内含子23和24均保留，且MYBPC3表达显著降低，与单倍体不足一致。与其他MYBPC3始祖变体的比较分析突出了表型表达的差异，特别是在左心室壁厚度和临床结局方面。本研究确定c.2309-2 A>G为意大利MYBPC3始祖突变，增强了对HCM遗传学和区域始祖效应的理解。这些发现强调了对MYBPC3 c.2309-2 A>G携带者进行靶向基因筛查和个性化管理的重要性。
