Mutaciones en el gen de la cadena pesada de la betamiosina en pacientes con miocardiopatía hipertrófica / Beta-myosin heavy-chain gene mutations in patients with hypertrophic cardiomyopathy

RESUMEN

Introducción y objetivos. Determinar la frecuencia de mutaciones en el gen de la cadena pesada de la betamiosina (MYH7) en una cohorte de pacientes con miocardiopatía hipertrófica (MCH) y en sus familiares, y analizar la correlación entre genotipo y fenotipo. Métodos. Detección de polimorfismo en la conformación de hebras monocatenarias y secuenciación de fragmentos con movilidad anormal del gen MYH7 en 128 casos índice consecutivos con MCH. Comparación de fenotipo entre pacientes con y sin mutaciones y descripción del fenotipo de las familias identificadas. Resultados. Identificamos 11 mutaciones en 13 familias (10%), 7/11 previamente descritas. La mutación I736T se identificó en 3 familias y la A797T en 2. Un caso presentó 2 mutaciones (I736T y R787H). Las mutaciones fueron más frecuentes en pacientes con antecedentes familiares de muerte súbita (31%) y con hipertrofia severa (39% con grosor ≥ 30 mm). Había mutación en 29 de 42 miembros de las 13 familias, incluidos 6 (20%) portadores sanos (edad ≤ 36 años). Había antecedentes de muerte súbita en 9 familiares de 4 familias (4 en 2 familias con I736T, uno con A797T, uno con R870H y 2 con A901P). Conclusiones. Las mutaciones en MYH7 aparecen en un 10% de nuestras familias y son más frecuentes cuando hay antecedentes familiares de muerte súbita o hipertrofia severa. La mayor parte había sido descrita previamente y algunas se repiten en varias familias. Ciertas mutaciones muestran una correlación genotipo-fenotipo estable, mientras que en otras, las marcadas diferencias entre casos índice y familiares hacen sospechar la presencia de factores genéticos adicionales que debemos identificar

ABSTRACT

Introduction and objectives. To determine the frequency of mutations in the beta-myosin heavy-chain gene (MYH7) in a cohort of patients with hypertrophic cardiomyopathy (HCM) and their families, and to investigate correlations between genotype and phenotype. Methods. Single-strand conformation polymorphism analysis and sequencing of fragments with abnormal MYH7 gene mobility were carried out in 128 consecutive index patients with HCM. The phenotypes of patients with and without mutations were compared and the phenotypes of identified families were recorded. Results. A total of 11 mutations were found in 13 families (10%); 7/11 had been previously described. The I736T mutation was found in three families and the A797T in two. One patient had two mutations (i.e., I736T and R787H). Mutations were more frequent in patients with a family history of sudden death (31%) and in those with severe hypertrophy (39% had a thickness ≥ 30 mm). Mutations were found in 29 of 42 members of the 13 families, including six family members (20%) who were healthy carriers and aged ≤ 36 years. Sudden death had occurred in eight members of four families four in two families with the I736T mutation, one in a family with A797T, one in a family with R870H, and two in a family with A901P. Conclusions. MYH7 mutations were present in 10% of our families. Mutations were more frequent in patients with a family history of sudden death and in those with severe hypertrophy. Most mutations had been described previously. Some appeared in several families. For some mutations, the correlation between genotype and phenotype was stable, while for others, there were marked differences between the phenotypes of the index patients and their relatives, suggesting the presence of additional genetic factors that have yet to be identified