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Introduction and objectives: Hypertrophic cardiomyopathy (HCM) is a genetically and phenotypically heterogeneous disease; there is still a large proportion of patients with no identified disease-causing mutation. Although the majority of mutations are found in the MYH7 and MYBPC3 genes, mutations in Z-disk-associated proteins have also been linked to HCM. Methods: We assessed a small family with HCM based on family history, physical examination, 12-lead ECG, echocardiogram and magnetic resonance imaging. After exclusion of mutations in eleven HCM disease genes, we performed direct sequencing of the TCAP gene encoding the Z-disk protein titin-cap (also known as telethonin). Results: We present a novel TCAP mutation in a small family affected by HCM. The identified p.C57W mutation showed a very low population frequency, as well as high conservation across species. All of the bioinformatic prediction tools used considered this mutation to be damaging/deleterious. Family members were screened for this new mutation and a co-segregation pattern was detected. Both affected members of this family presented with late-onset HCM, moderate asymmetric left ventricular hypertrophy, atrial fibrillation and heart failure with preserved ejection fraction and low risk of sudden cardiac death. Conclusions: We present evidence supporting the classification of the TCAP p.C57W mutation, encoding the Z-disk protein titin-cap/telethonin as a new likely pathogenic variant of hypertrophic cardiomyopathy, with a specific phenotype in the family under analysis. Resumo: Introdução e objetivos: A miocardiopatia hipertrófica (HCM) é uma doença genética e fenotipicamente heterogénea, existindo ainda uma grande proporção de doentes sem uma mutação patogénica identificada. Embora a maioria das mutações seja encontrada nos genes MYH7 e MYBPC3, mutações em proteínas associadas ao disco Z também foram associadas à HCM. Métodos: Avaliámos uma pequena família com HCM com base na história familiar e exame objetivo, eletrocardiograma de 12 derivações, ecocardiograma e ressonância magnética. Após exclusão de mutações em 11 genes causadores de HCM, realizámos a sequenciação direta do gene TCAP que codifica a proteína titin-cap do disco-Z (também conhecida como teletonina). Resultados: Relatamos aqui uma nova mutação do gene TCAP numa pequena família com HCM. A mutação identificada, p.C57W, mostrou uma frequência populacional muito baixa, bem como alta conservação entre as espécies. Todas as ferramentas de previsão de bioinformática usadas previram que essa mutação seria funcionalmente prejudicial. A presença desta nova mutação foi avaliada nos outros membros da família, tendo-se detetado um padrão de cossegregação. Ambos os membros da família afetados apresentaram HCM de início tardio, com hipertrofia ventricular esquerda assimétrica moderada, fibrilhação auricular e insuficiência cardíaca com fracão de ejeção preservada, com baixo risco de morte súbita cardíaca. Conclusão: Apresentamos evidência que suporta a classificação da mutação TCAP p.C57W, que codifica a proteína titin-cap do disco-Z (teletonina), como uma nova variante provavelmente patogénica da HCM, com um perfil fenotípico específico na família analisada.

Introduction and Objectives: Hypertrophic cardiomyopathy (HCM) is a genetically and phenotypically heterogeneous disease; there is still a large proportion of patients with no identified disease-causing mutation. Although the majority of mutations are found in the MYH7 and MYBPC3 genes, mutations in Z-disk-associated proteins have also been linked to HCM., Methods: We assessed a small family with HCM based on family history, physical examination, 12-lead ECG, echocardiogram and magnetic resonance imaging. After exclusion of mutations in eleven HCM disease genes, we performed direct sequencing of the TCAP gene encoding the Z-disk protein titin-cap (also known as telethonin)., Results: We present a novel TCAP mutation in a small family affected by HCM. The identified p.C57W mutation showed a very low population frequency, as well as high conservation across species. All of the bioinformatic prediction tools used considered this mutation to be damaging/deleterious. Family members were screened for this new mutation and a co-segregation pattern was detected. Both affected members of this family presented with late-onset HCM, moderate asymmetric left ventricular hypertrophy, atrial fibrillation and heart failure with preserved ejection fraction and low risk of sudden cardiac death., Conclusions: We present evidence supporting the classification of the TCAP p.C57W mutation, encoding the Z-disk protein titin-cap/telethonin as a new likely pathogenic variant of hypertrophic cardiomyopathy, with a specific phenotype in the family under analysis., (Copyright © 2020 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)