Factores que influyen en la expresión fenotípica de la miocardiopatía hipertrófica en portadores genéticos / Factors influencing the phenotypic expression of hypertrophic cardiomyopathy in genetic carriers

Introducción y objetivos: La miocardiopatía hipertrófica (MCH) es una enfermedad con expresión variable, causada principalmente por mutaciones en genes sarcoméricos, aunque otros factores podrían estar modulando el fenotipo. El objetivo es determinar si el sexo, la hipertensión arterial o la actividad física son moduladores de la gravedad de la enfermedad y establecer su papel en la penetrancia en relación con la edad al diagnóstico de la MCH. Métodos: Se evaluó a 272 individuos (media de edad, 49 ± 17 años; el 57% varones) procedentes de 72 familias con mutación causal y se estudió la relación del sexo, la hipertensión y la actividad física con la hipertrofia ventricular izquierda. Resultados: La proporción de afectados aumenta con la edad. Se diagnosticó a los varones una mediana ajustada de 12,5 años (IC95%, -17,52 a -6,48; p < 0,001) antes que a las mujeres. A los pacientes hipertensos, se les diagnosticó MCH una mediana ajustada de 10,8 años (IC95%, 6,28-17,09; p < 0,001) más tarde que a los normotensos. A los individuos que hacían ejercicio, se los diagnosticó significativamente antes (mediana ajustada, 7,3 años; IC95%, -14,49 a -1,51; p = 0,016). El sexo, la hipertensión y el ejercicio no resultaron significativamente asociados con la gravedad de la hipertrofia del ventrículo izquierdo. Los factores explorados no influyen en la supervivencia ajustada libre de muerte súbita y el evento combinado. Conclusiones: Se diagnostica a los varones y los deportistas portadores de mutaciones sarcoméricas antes que a las mujeres y los individuos sedentarios. Los portadores de mutaciones sarcoméricas hipertensos tienen un retraso en el diagnóstico. El sexo, la hipertensión y el ejercicio no se asocian con la gravedad de la enfermedad en portadores de mutaciones causales de MCH (AU)

Introduction and objectives: Hypertrophic cardiomyopathy (HCM) is a disorder with variable expression. It is mainly caused by mutations in sarcomeric genes but the phenotype could be modulated by other factors. The aim of this study was to determine whether factors such as sex, systemic hypertension, or physical activity are modifiers of disease severity and to establish their role in age-related penetrance of HCM. Methods: We evaluated 272 individuals (mean age 49 ± 17 years, 57% males) from 72 families with causative mutations. The relationship between sex, hypertension, physical activity, and left ventricular hypertrophy was studied. Results: The proportion of affected individuals increased with age. Men developed the disease 12.5 years earlier than women (adjusted median, 95%CI, -17.52 to -6.48; P < .001). Hypertensive patients were diagnosed with HCM later (10.8 years of delay) than normotensive patients (adjusted median, 95%CI, 6.28-17.09; P < .001). Individuals who performed physical activity were diagnosed with HCM significantly earlier (7.3 years, adjusted median, 95%CI, -14.49 to -1.51; P = .016). Sex, hypertension, and the degree of physical activity were not significantly associated with the severity of left ventricular hypertrophy. Adjusted survival both free from sudden death and from the combined event were not influenced by any of the exploratory variables. Conclusions: Men and athletes who are carriers of sarcomeric mutations are diagnosed earlier than women and sedentary individuals. Hypertensive carriers of sarcomeric mutations have a delayed diagnosis. Sex, hypertension, and physical activity are not associated with disease severity in carriers of HCM causative mutations (AU)

Factors Influencing the Phenotypic Expression of Hypertrophic Cardiomyopathy in Genetic Carriers.

INTRODUCTION AND OBJECTIVES: Hypertrophic cardiomyopathy (HCM) is a disorder with variable expression. It is mainly caused by mutations in sarcomeric genes but the phenotype could be modulated by other factors. The aim of this study was to determine whether factors such as sex, systemic hypertension, or physical activity are modifiers of disease severity and to establish their role in age-related penetrance of HCM. METHODS: We evaluated 272 individuals (mean age 49 ± 17 years, 57% males) from 72 families with causative mutations. The relationship between sex, hypertension, physical activity, and left ventricular hypertrophy was studied. RESULTS: The proportion of affected individuals increased with age. Men developed the disease 12.5 years earlier than women (adjusted median, 95%CI, -17.52 to -6.48; P < .001). Hypertensive patients were diagnosed with HCM later (10.8 years of delay) than normotensive patients (adjusted median, 95%CI, 6.28-17.09; P < .001). Individuals who performed physical activity were diagnosed with HCM significantly earlier (7.3 years, adjusted median, 95%CI, -14.49 to -1.51; P = .016). Sex, hypertension, and the degree of physical activity were not significantly associated with the severity of left ventricular hypertrophy. Adjusted survival both free from sudden death and from the combined event were not influenced by any of the exploratory variables. CONCLUSIONS: Men and athletes who are carriers of sarcomeric mutations are diagnosed earlier than women and sedentary individuals. Hypertensive carriers of sarcomeric mutations have a delayed diagnosis. Sex, hypertension, and physical activity are not associated with disease severity in carriers of HCM causative mutations.

Nueva mutación fundadora en MYBPC3: comparación fenotípica con la mutación de MYBPC3 más frecuente en España / A novel founder mutation in MYBPC3: Phenotypic comparison with the most prevalent MYBPC3 mutation in Spain

Introducción y objetivos: Las mutaciones en MYBPC3 son causa de miocardiopatía hipertrófica (MCH). A pesar de que la mayoría de ellas producen una proteína truncada, la gravedad del fenotipo es diversa. Se describe el fenotipo clínico de una nueva mutación en MYBPC3, p.Pro108Alafs*9, presente en 13 familias del sur de España, y se compara con la mutación de MYBPC3 con mayor prevalencia en dicha región (c.2308 + 1 G > A). Métodos: Se estudió a 107 familiares de 13 casos índice que tenían diagnóstico de MCH y portaban la mutación p.Pro108Alafs*9. Se realizó un análisis del árbol genealógico, junto con una evaluación clínica y determinación del genotipo. Resultados: Se identificó en total a 54 portadores de la mutación p.Pro108Alafs*9, de los que 39 tenían MCH. Hubo 5 casos de muerte súbita en las 13 familias. La penetrancia de la enfermedad aumentaba a medida que se incrementaba la edad, y los pacientes con MCH fueron con más frecuencia varones, y estos contrajeron la enfermedad más precozmente que las mujeres. El fenotipo fue similar en la p.Pro108Alafs*9 y la c.2308 + 1 G > A, pero se observaron diferencias en varios factores de riesgo y en la supervivencia. Hubo tendencia a mayor masa ventricular izquierda en la p.Pro108Alafs*9 que en la c.2308 + 1G > A. La resonancia magnética cardiaca reveló una extensión y un patrón de fibrosis similares en ambas. Conclusiones: La mutación p.Pro108Alafs*9 se asoció a MCH, alta penetrancia y aparición de la enfermedad a mediana edad (AU)

Introduction and objectives: Mutations in MYBPC3 are the cause of hypertrophic cardiomyopathy (HCM). Although most lead to a truncating protein, the severity of the phenotype differs. We describe the clinical phenotype of a novel MYBPC3 mutation, p.Pro108Alafs*9, present in 13 families from southern Spain and compare it with the most prevalent MYBPC3 mutation in this region (c.2308 + 1 G > A). Methods: We studied 107 relatives of 13 index cases diagnosed as HCM carriers of the p.Pro108Alafs*9 mutation. Pedigree analysis, clinical evaluation, and genotyping were performed. Results: A total of 54 carriers of p.Pro108Alafs*9 were identified, of whom 39 had HCM. There were 5 cases of sudden death in the 13 families. Disease penetrance was greater as age increased and HCM patients were more frequently male and developed disease earlier than female patients. The phenotype was similar in p.Pro108Alafs*9 and in c.2308 + 1 G > A, but differences were found in several risk factors and in survival. There was a trend toward a higher left ventricular mass in p.Pro108Alafs*9 vs c.2308 + 1G > A. Cardiac magnetic resonance revealed a similar extent and pattern of fibrosis. Conclusions: The p.Pro108Alafs*9 mutation is associated with HCM, high penetrance, and disease onset in middle age (AU)

A Novel Founder Mutation in MYBPC3: Phenotypic Comparison With the Most Prevalent MYBPC3 Mutation in Spain.

INTRODUCTION AND OBJECTIVES: Mutations in MYBPC3 are the cause of hypertrophic cardiomyopathy (HCM). Although most lead to a truncating protein, the severity of the phenotype differs. We describe the clinical phenotype of a novel MYBPC3 mutation, p.Pro108Alafs*9, present in 13 families from southern Spain and compare it with the most prevalent MYBPC3 mutation in this region (c.2308+1 G>A). METHODS: We studied 107 relatives of 13 index cases diagnosed as HCM carriers of the p.Pro108Alafs*9 mutation. Pedigree analysis, clinical evaluation, and genotyping were performed. RESULTS: A total of 54 carriers of p.Pro108Alafs*9 were identified, of whom 39 had HCM. There were 5 cases of sudden death in the 13 families. Disease penetrance was greater as age increased and HCM patients were more frequently male and developed disease earlier than female patients. The phenotype was similar in p.Pro108Alafs*9 and in c.2308+1 G>A, but differences were found in several risk factors and in survival. There was a trend toward a higher left ventricular mass in p.Pro108Alafs*9 vs c.2308+1G>A. Cardiac magnetic resonance revealed a similar extent and pattern of fibrosis. CONCLUSIONS: The p.Pro108Alafs*9 mutation is associated with HCM, high penetrance, and disease onset in middle age.