Sarcomeric hypertrophic cardiomyopathy: Genetic profile in a Portuguese population

Sarcomeric hypertrophic cardiomyopathy has heterogeneous phenotypic expressions, of which sudden cardiac death is the most feared. A genetic diagnosis is essential to identify subjects at risk in each family. The spectrum of disease-causing mutations in the Portuguese population is unknown. Seventy-seven unrelated probands with hypertrophic cardiomyopathy were systematically screened for mutations by PCR and sequencing of five sarcomeric genes: MYBPC3, MYH7, TNNT2, TNNI3 and MYL2. Familial cosegregation analysis was performed in most patients. Thirty-four different mutations were identified in 41 (53%) index patients, 71% with familial hypertrophic cardiomyopathy. The most frequently involved gene was MYBPC3 (66%) with 22 different mutations (8 novel) in 27 patients, followed by MYH7 (22%), TNNT2 (12%) and TNNI3 (2.6%). In three patients (7%), two mutations were found in MYBPC3 and/or MYH7. Additionally, 276 relatives were screened, leading to the identification of a mean of three other affected relatives for each pedigree with the familial form of the disease. Disease-associated mutations were identified mostly in familial hypertrophic cardiomyopathy, corroborating the idea that rarely studied genes may be implicated in sporadic forms. Private mutations are the rule, MYBPC3 being the most commonly involved gene. Mutations in MYBPC3 and MYH7 accounted for most cases of sarcomere-related disease. Multiple mutations in these genes may occur, which highlights the importance of screening both. The detection of novel mutations strongly suggests that all coding regions should be systematically screened. Genotyping in hypertrophic cardiomyopathy enables a more precise diagnosis of the disease, with implications for risk stratification and genetic counseling. A miocardiopatia hipertrófica sarcomérica (MH) tem expressão fenotípica heterogénea, sendo a morte súbita cardíaca a mais temida. O diagnóstico genético é fundamental para identificar os indivíduos em risco em cada família. O perfil genético da doença é desconhecido na população portuguesa. Estudaram-se geneticamente 77 doentes-índice com MH, não-relacionados, pesquisando-se, por PCR e sequenciação, mutações nos genes MYBPC3, MYH7, TNNT2, TNNI3 e MYL2. Efetuou-se análise de co-segregação familiar na maioria dos doentes. Identificaram-se 34 mutações diferentes em 41 doentes-índice (53%), 71% com MH familiar. O gene mais frequentemente envolvido foi o MYBPC3 (66%), identificando-se 22 mutações diferentes (8 nov