👤 Antonio Pizzuti

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. Show less

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac muscle disease characterized by clinical and genetic heterogeneity. Genetic testing can reveal the presence of disease-causing variants in genes encoding sarcomere proteins. However, it yields inconclusive or negative results in 40-60% of HCM cases, owing to, among other causes, technical limitations such as the inability to detect pathogenic intronic variants. Therefore, we aimed to increase the diagnostic yield of molecular analysis for HCM by improving the Show less

Tricuspid atresia (TriAt), the third most common cyanotic congenital heart defect (CHD), consists of complete lack of tricuspid valve formation, with no connection between the right atrium and the right ventricle. To date, the genetic mechanism responsible of TriAt is still obscure. However, animal models have suggested a role of cardiogenic Zfpm2/Fog2 and Hey2 genes in the pathogenesis of TriAt. Therefore, we screened 40 individuals affected by nonsyndromic TriAt for ZFPM2/FOG2 and HEY2 gene mutations. No pathogenetic mutation has been identified, thus failing to demonstrate a major role of ZFPM2/FOG2 and HEY2 genes in the pathogenesis of human TriAt. Show less