Caracterização genotípica e fenotípica de famílias portadoras de cardiomiopatia hipertrófica
Caracterização genotípica e fenotípica de famílias portadoras de cardiomiopatia hipertrófica
Data
2016
Autores
Rafael, Julianny Freitas
Journal Title
Journal ISSN
Volume Title
Publisher
Instituto Nacional de Cardiologia
Resumo
Introdução: A cardiomiopatia hipertrófica (CMH) é um doença genética, autossômica dominante, causada por mutações nos genes que codificam para as proteínas do sarcômero, sendo a principal causa de morte súbita cardíaca (MSC) em jovens e atletas de alto nível. Estudos têm demonstrado um pior prognóstico associado a mutações específicas. A relação entre o genótipo e o fenótipo da CMH, tem sido alvo de diversos estudos desde a descoberta do caráter genético da doença. O objetivo desse trabalho é caracterizar genotípica e fenotipicamente pacientes portadores de CMH e seus familiares. Metodologia: Os probandos com diagnóstico clínico de CMH foram submetidos ao diagnóstico genético através do sequenciamento direto dos três principais genes relacionados à essa patologia, MYH7, MYBPC3 e TNNT2. Através de entrevista foi construído heredograma. Os probandos e familiares foram examinados através de ecocardiograma transtorácico, eletrocardiograma e Holter de 24 horas, e as mutações encontradas nos probandos foram investigadas nos familiares. Foram avaliadas o risco de MSC dos indivíduos e a patogenicidade das mutações encontradas através de ferramentas computacionais. Resultados: Foram analisadas duas famílias de indivíduos portadores de CMH. No probando da família A foi identificado a mutação p.Arg453Cys na cadeia pesada da -miosina,. Este era portador de CMH e possuia história de morte súbita cardíaca abortada, com implante de CDI para profilaxia secundária. Seu ecocardiograma evidenciava hipertrofia septal assimétrica do tipo curva reversa, sem gradiente de via de saída do ventrículo esquerdo. A análise da família demonstra alta incidência de CMH com indivíduos afetados em todas as gerações e alta mortalidade. Todos os indivíduos portadores do alelo mutado apresentavam fenótipo de CMH, exceto uma criança de 13 anos (alta penetrância). A hipertrofia septal tipo curva reversa como o tipo de hipertrofia predominante nesta família. No segundo probando (família B), com manifestação severa da doença, foi identificada uma dupla mutação em heterozigose no gene MYBPC3, Glu542Gln e Asp610His. Seu ecocardiograma demonstrava hipertrofia septal assimétrica, tipo curva reversa, com septo medindo 3,9 cm. Além disso havia relato de síncope, com implante de CDI para profilaxia primária, com alto risco de MSC. A análise de seus familiares demonstrou que os alelos Glu542Gln e Asp610His são de origem paterna e materna, respectivamente. Nenhum dos familiares portadores dos alelos individuais apresentaram manifestação clínica de CMH. Conclusão: Nossos dados sugerem que a mutação Arg453Cys na cadeia pesada da miosina é responsável pela manifestação e gravidade da expressão da CMH na família A, e que a dupla mutação no gene MYBPC3, seria determinante para o desenvolvimento da forma grave de CMH no probando B. A provável associação patogênica das mutações Glu542Gln e Asp6010His, foi primeiramente descrita neste estudo.
Introduction: Hypertrophic cardiomyopathy (HCM) is a genetic disease, autosomal dominant, caused by mutations in the genes coding for sarcomere proteins, being the major cause of sudden cardiac death (SCD) in young high-level athletes. Studies have shown a worse prognosis associated with specific mutations. The relationship between genotype and phenotype of HCM has been the subject of several studies since the discovery of the genetic nature of the disease. The aim of this study is to characterize genotypic and phenotypic patients with hypertrophic cardiomyopathy and their families. Methodology: The probands with a clinical diagnosis of HCM underwent genetic diagnosis through direct sequencing of the three main genes related to this disease, MYH7, MYBPC3 and TNNT2. Through interview it was built pedigree. The probands and family were examined by transthoracic echocardiography, electrocardiogram and Holter 24 hours, and the mutations found in probands were investigated in the family. We evaluated the risk of SCD of individuals and the pathogenicity of these mutations using computational tools. Results: We analyzed two families of individuals with HCM. In family's A proband was identified the p.Arg453Cys mutation in the β-myosin heavy chain. He had CMH and a history of SCD aborted with ICD implantation for secondary prophylaxis. His echocardiogram showed asymmetric septal hypertrophy type reverse curve without outflow tract gradient of the left ventricle. The family analysis shows high incidence of CMH with affected individuals in every generation and high mortality. All individuals carriers of the variant allele presented HCM phenotype, except a child of 13 years old (high penetrance). The reverse curve septal hypertrophy was the predominant type of hypertrophy. In the second proband (family B), with severe manifestation of the disease, a double heterozygous mutation was identified (p.Glu542Gln and p.Asp610His) in MYBPC3. His echocardiogram showed asymmetric septal hypertrophy, type reverse curve, with septum measuring 3,9cm. Also he had syncope report with ICD implantation for primary prevention with high risk of SCD. The family analysis showed that the Glu542Gln and Asp610His alleles have paternal and maternal origin, respectively. No family members carrier of individual alleles showed clinical signs of HCM. Conclusion: Our data suggest that p.Arg453Cys mutation in the β myosin heavy chain is responsible for the manifestation and severity of expression of HCM in the family A, and that the double heterozygous mutation in MYBPC3 gene, would be crucial to the development of the severe form of HCM in the proband B. The probable pathogenic association of p.Glu542Gln and p.Asp6010His mutations, was first described in this study.
Introduction: Hypertrophic cardiomyopathy (HCM) is a genetic disease, autosomal dominant, caused by mutations in the genes coding for sarcomere proteins, being the major cause of sudden cardiac death (SCD) in young high-level athletes. Studies have shown a worse prognosis associated with specific mutations. The relationship between genotype and phenotype of HCM has been the subject of several studies since the discovery of the genetic nature of the disease. The aim of this study is to characterize genotypic and phenotypic patients with hypertrophic cardiomyopathy and their families. Methodology: The probands with a clinical diagnosis of HCM underwent genetic diagnosis through direct sequencing of the three main genes related to this disease, MYH7, MYBPC3 and TNNT2. Through interview it was built pedigree. The probands and family were examined by transthoracic echocardiography, electrocardiogram and Holter 24 hours, and the mutations found in probands were investigated in the family. We evaluated the risk of SCD of individuals and the pathogenicity of these mutations using computational tools. Results: We analyzed two families of individuals with HCM. In family's A proband was identified the p.Arg453Cys mutation in the β-myosin heavy chain. He had CMH and a history of SCD aborted with ICD implantation for secondary prophylaxis. His echocardiogram showed asymmetric septal hypertrophy type reverse curve without outflow tract gradient of the left ventricle. The family analysis shows high incidence of CMH with affected individuals in every generation and high mortality. All individuals carriers of the variant allele presented HCM phenotype, except a child of 13 years old (high penetrance). The reverse curve septal hypertrophy was the predominant type of hypertrophy. In the second proband (family B), with severe manifestation of the disease, a double heterozygous mutation was identified (p.Glu542Gln and p.Asp610His) in MYBPC3. His echocardiogram showed asymmetric septal hypertrophy, type reverse curve, with septum measuring 3,9cm. Also he had syncope report with ICD implantation for primary prevention with high risk of SCD. The family analysis showed that the Glu542Gln and Asp610His alleles have paternal and maternal origin, respectively. No family members carrier of individual alleles showed clinical signs of HCM. Conclusion: Our data suggest that p.Arg453Cys mutation in the β myosin heavy chain is responsible for the manifestation and severity of expression of HCM in the family A, and that the double heterozygous mutation in MYBPC3 gene, would be crucial to the development of the severe form of HCM in the proband B. The probable pathogenic association of p.Glu542Gln and p.Asp6010His mutations, was first described in this study.
Description
Palavras-chave
Cardiopatia hipertrópica, Mutação genética, Genótipo, Fenótipo, Hypertrophic cardiomyopathy, Genetic mutation, Genotype, Phenotype
Citação
Rafael JF.Caracterização genotípica e fenotípica de famílias portadoras de cardiomiopatia hipertrófica. Rio de Janeiro. Dissertação [Mestrado Profissional em Ciências Cardiovasculares] - Instituto Nacional de Cardiologia; 2016.