P4729Spectrum of clinical phenotypes and genotypes in 5310 patients with hypertrophic cardiomyopathy

Abstract

Background: Hypertrophic cardiomyopathy (HCM), with a prevalence of about 1 in 500 individuals, is the most common genetic cardiovascular disease. Despite the knowledge about the different causal genes, the relationship between individual genotypes and phenotypes is incomplete. The aim of this study was to create a comprehensive picture on the clinical outcomes of sarcomere mutation positive patients to support better personalized management of HCM patients. Methods and Results: Firstly, we performed a retrospective study in 88 genotyped HCM patients of our registry and analyzed their genotype-phenotype correlations. Next, we retrieved PubMed/Medline literature on genotype-phenotype correlation in patients with HCM and mutations in MYBPC3, MYH7, TNNT2 and TNNI3 as well as HCM patients without sarcomeric mutations. We reviewed all studies that passed selection criteria and performed a meta-analysis. Together, 47 studies with 5310 HCM patients could be included. The average frequency of mutations in MYBPC3 (20%) and MYH7 (14%) was higher than in TNNT2 and TNNI3 (2% each). The mean age of HCM onset for MYH7 and TNNT2 mutation carriers was the beginning of the fourth decade, significantly earlier than in patients without sarcomeric mutations. A high male proportion was observed in TNNT2 (69%), MYBPC3, and mutation negative group (62% each). Cardiac conduction disease, ventricular arrhythmia, left ventricular outflow tract obstruction, and heart transplantation (HTx) rate were higher in HCM patients with MYH7 mutations in comparison to MYBPC3 (p<0.05). Furthermore, sudden cardiac death (SCD) was significantly higher in patients with sarcomeric mutations (p<0.01). Conclusion(s): This comprehensive genotype-phenotype analysis show that the age at disease onset of HCM patients with sarcomeric mutations is earlier and leads to a more severe phenotype than in patient without such mutations. Furthermore, patients with MYH7 and TNNT2 mutations are more susceptible to arrhythmia and SCD. The present study further supports the clinical interpretation of sarcomeric mutations in HCM patients and help physicians in decision making procedures such as ICD implantation or reassurement of patients with specific benign mutations.