Cohort of patients with hypertrophic cardiomyopathy and alpha tropomyosin 1 variants followed up at a national reference center

Abstract

Abstract Background Hypertrophic cardiomyopathy (HCM), the most common inherited cardiac condition, is mainly caused by pathogenic variants in sarcomeric genes. Alpha tropomyosin gene (TPM1) account for a small percentage (1–5%) of HCM cases with ∼20 relevant variants described so far related to this condition. However, TPM1–hypertrophic cardiomyopathy is thought to be associated with high rates of heart failure and sudden death (SD). Purpose To describe the phenotype and genotype of a cohort of adult and pediatric patients with HCM and variants in TPM1 followed up in an inherited cardiovascular disease program of a national reference center. Methods Patients with HCM and TPM1 variants potentially related to the phenotype were retrospectively identified. Genetic test was performed by next generation sequencing panels or clinical exome. Clinical data, any need of intervention (obstruction relief, device implantation, heart transplant) and major adverse cardiovascular events were collected from medical records. We performed co-segregation studies whenever possible. Predictive models in order to support the possible pathogenicity of the variants were also applied. Results We identified 13 individuals (54% females) from 11 families with HCM and variants in TPM1. 12 patients had phenotype and one was a carrier. 5 out of 12 patients (42%) were diagnosed before the age of 12 years, all with severe phenotype. The most frequent pattern was asymmetric septal hypertrophy, with a mean thickness of the septum of 22 mm (range 14–37). 4 cases were obstructive, of which 3 required surgical myectomy. 4 patients required an implanted cardiac defibrillator (ICD), all in childhood. One was in secondary prevention after an aborted SD in a 12-year-old girl. 3 appropriate therapies were recorded in 2 patients during follow-up. A girl underwent heart transplantation at the age of 12 because of angina at rest. At last evaluation 67% were symptomatic, with 3 patients in functional class II and 5 patients in functional class III-IV/IV. 8 missense variants in TPM1 were identified in the 11 families (table 1). All variants are described in Clinvar as variants of unknown significance (VUS). They appear at a very low frequency (<0.01%) or are absent in general population and predictive models of protein structure and functionality (PreditProtein) indicate an impact on the structure of the protein, supporting their possible pathogenicity. Figure 1 shows a diagram of the variants position within TPM1 gen. Cossegregation data and the presence of the same variant in non_related families allowed us to reclassify 4 variants as “likely pathogenic”. Conclusion This study provides cosegregation data and “in silico” analysis of the potential functional impact of several TPM1 variants, supporting their pathogenicity. In our cohort, HCM related to TMP1 variants is associated with high penetrance (92%), early onset and poor clinical course in childhood and youth. Funding Acknowledgement Type of funding sources: None. Figure 1