Two founder MYBPC3 splicing variants in Italian HCM patients cause similar phenotype and outcome but show a later diagnosis age and indolent clinical course.
Do specific founder MYBPC3 splicing variants (c.1458-1G>A and c.3331-1G>A) result in a different clinical course or outcome compared to other sarcomeric gene mutations in patients with hypertrophic cardiomyopathy?
Two recurrent MYBPC3 splicing variants in Italian HCM patients are associated with a later age of diagnosis but similar long-term clinical outcomes compared to other sarcomeric mutations, suggesting a founder effect with an indolent initial course.
Tasa de eventos absoluta: 0% vs 0%
Abstract Background Mutations in MYBPC3 gene, which encodes the cardiac isoform of myosin-binding protein C, are associated to a variety of cardiological phenotypes, most notably hypertrophic cardiomyopathy (HCM), for which it is one of the most common genetic causes. Aim The aim of our study is to present the genetic findings and clinical manifestation of two specific MYBPC3 splicing variants (c.1458-1GA and c.3331-1GA), which are classified as pathogenic and pathogenic/likely pathogenic, respectively, according to the Clinvar dataset. These variants, however, are absent in population databases. Methods We collect clinical data and cardiological assessment on patients with HCM carrying these two variants, from eight cardiology Units of our region. Genetic tests were carried out using the targeted next-generation sequencing (tNGS) approach, and additional haplotype analysis as well as functional studies with bioinformatic tool prediction were performed. To compare the clinical course of these patients, we used a cohort of subjects with a clinical diagnosis HCM followed at our center. Results We identified 44 patients carrying the c.1458-1GA variant and 18 patients with the c.3331-1GA variant. Haplotype analysis, conducted to investigate a potential common ancestor, suggested a founder effect for these mutations, which may explain the high recurrence of these splicing variants in the Italian population and specifically in our region. Functional analysis, performed to assess the actual pathogenicity of these variants, indicated significant splicing alterations ranging from exon skipping to activation of a cryptic splice site. When compared to 179 HCM patients carrying pathogenic/likely pathogenic (LP/P) variants in sarcomeric genes, carriers of both our splicing MYBPC3 variants were diagnosed at a later age, which is consistent with a more indolent clinical course typically seen with mutations that have a founder effect. No significant differences were observed in clinical and echocardiographic characteristics, nor in the incidence of major cardiac events (composite of death, major arrhythmic events, and worsening heart failure) during a comparable follow-up. (Figure 2). Even when considering 119 HCM patients with P/LP MYBPC3 variants, no significant differences were found in terms of phenotypic expression, clinical progression or survival. Conclusion This study presents, for the first time, the clinical characteristics of a cohort of patients with two recurrent MYBPC3 variants. These patients exhibited a relatively indolent clinical course, which is consistent with the founder effect of these variants, and no significant differences in terms of phenotype and outcome were observed compared to other mutations in MYBC3 or in sarcomeric genes. The identification and investigation of variants with such high prevalence in the population may be crucial for future developments in gene therapy.Survival curves between analyzed groups
Fanciullo et al. (Sat,) reported a other. Two founder MYBPC3 splicing variants in Italian HCM patients cause similar phenotype and outcome but show a later diagnosis age and indolent clinical course.