Defining the cardiac alpha-tropomyosinGenotype-phenotype correlations oninherited heart diseases

Abstract

Background: Cardiac alpha-tropomyosin (encoded by TPM1 gene) is one priority sarcomere gene; nonetheless, most of the carriers are restricted to a single family or few index cases by each variant. TPM1 has been associated with the development of different forms of inherited cardiomyopathy, and congenital heart defects. Objective: To analyze the genotype-phenotype correlation in carriers of TPM1 variants. Methods: Genotype-phenotype correlation analysis was performed based on medical records from several European centers. Pathogenicity and molecular characteristics on each variant, clinical features, pedigrees, age of diagnosis, and prognosis were analyzed. Results: Data on 257 TPM1 variants was systematized, allowing changes in the pathogenicity of 87 variants, and the identification of functional domains overrepresented by phenotype. A novel cohort with 380 unpublished TPM1 patients, including the founder variant p. Arg21Leu shows in general a favorable prognosis, and late-onset manifestations. An earlier age of diagnosis is observed in families with dilated/left ventricle noncompaction cardiomyopathy. Conclusions: Genetic results from families with inherited heart diseases associated with TPM1 variants can be useful for clinical decision making process and genetic counseling.