Manuel Hermida-Prieto

Insights into genotype–phenotype correlation in hypertrophic cardiomyopathy. Findings from 18 Spanish families with a single mutation in MYBPC3

Background Mutations in the cardiac myosin-binding protein C (MYBPC3) gene are frequently found as a cause of hypertrophic cardiomyopathy (HCM). However, only a few studies have analysed genotype–phenotype correlations in small series of patients. The present study sought to determine the clinical characteristics, penetrance and prognosis of HCM with an identical mutation in MYBPC3. Methods 154 non-related patients with HCM (aged 55±16 years, 100 (64.9%) males) were studied. 18 (11.7%) were found to have an identical mutation in the MYBPC3 gene (IVS23+1G→A). Pedigree analysis, including both clinical evaluation and genotyping, was performed. Results 152 individuals (mean age 37±18 years, 53.3% males) from 18 families were evaluated. 65 carriers of the IVS23+1G→A mutation were identified, 61.5% of whom met HCM diagnostic criteria. Penetrance of the disease increased with age, with 50% affected at 46 years of age. Males tended to develop the disease earlier than females. 7 (15.6%) had systolic dysfunction. Compared with the rest of the HCM cohort, probands with the mutation had more hypertrophy and were younger at diagnosis. There was a trend towards a reduced survival free from sudden death (SD) (HR 1.71; 95% CI 0.98 to 2.98, p=0.059). There were 17 SD cases in 12 families with the mutation. Conclusions The MYBPC3 IVS23+1G→A mutation is associated with middle-age onset disease and poor outcome, with a significant proportion of patients developing systolic impairment and a high SD risk profile.

Mutational screening of phospholamban gene in hypertrophic and idiopathic dilated cardiomyopathy and functional study of the PLN –42 C>G mutation

Phospholamban is an endogenous sarcoplasmic reticulum calcium ATPase inhibitor with a regulatory effect on cardiac contraction/relaxation coupling. Mutations in the phospholamban gene (PLN) have been associated with primary cardiomyopathies.

Mutaciones en el gen de la cadena pesada de la betamiosina en pacientes con miocardiopatía hipertrófica

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 3 families and the A797T in 2. One patient had 2 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 6 family members (20%) who were healthy carriers and aged ≤36 years. Sudden death had occurred in 8 members of 4 families: four in 2 families with the I736T mutation, 1 in a family with A797T, 1 in a family with R870H, and 2 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

Screening mutations in myosin binding protein C3 gene in a cohort of patients with Hypertrophic Cardiomyopathy

BackgroundMyBPC3 mutations are amongst the most frequent causes of hypertrophic cardiomyopathy, however, its prevalence varies between populations. They have been associated with mild and late onset disease expression. Our objectives were to establish the prevalence of MyBPC3 mutations and determine their associated clinical characteristics in our patients.MethodsScreening by Single Strand Conformation Polymorphisms (SSCP) and sequencing of the fragments with abnormal motility of the MyBPC3 gene in 130 unrelated consecutive HCM index cases. Genotype-Phenotype correlation studies were done in positive families.Results16 mutations were found in 20 index cases (15%): 5 novel [D75N, V471E, Q327fs, IVS6+5G>A (homozygous), and IVS11-9G>A] and 11 previously described [A216T, R495W, R502Q (2 families), E542Q (3 families), T957S, R1022P (2 families), E1179K, K504del, K600fs, P955fs and IVS29+5G>A]. Maximum wall thickness and age at time of diagnosis were similar to patients with MYH7 mutations [25(7) vs. 27(8), p = 0.16], [46(16) vs. 44(19), p = 0.9].ConclusionsMutations in MyBPC3 are present in 15% of our hypertrophic cardiomyopathy families. Severe hypertrophy and early expression are compatible with the presence of MyBPC3 mutations. The genetic diagnosis not only allows avoiding clinical follow up of non carriers but it opens new possibilities that includes: to take preventive clinical decisions in mutation carriers than have not developed the disease yet, the establishment of genotype-phenotype relationship, and to establish a genetic diagnosis routine in patients with familial HCM.

Hypertrophic cardiomyopathy. A study of the troponin-T gene in 127 Spanish families.

The information available on the correlation between genotype and phenotype and the prognostic implications of different troponin-T gene mutations is sparse and, at times, contradictory. We studied the TNNT2 gene in 127 patients with hypertrophic cardiomyopathy and identified three mutations in patients from four families (3.1%): the Phe87Leu mutation, which has not been previously reported, the Arg278Cys mutation (two families) and the Asp271Ile mutation. Seven carriers of the Phe87Leu mutation (aged 29 to 52 years) were found to have mild hypertrophy (i.e., a wall thickness <16 mm). There were 11 deaths associated with the condition (seven sudden deaths), and four of those who died were aged between 14 and 16 years. No sudden deaths occurred in the other three families. In conclusion, troponin-T mutations were responsible for 3% of the hypertrophic cardiomyopathy cases in our study population. The Phe87Leu mutation was associated with only mild hypertrophy but with a high risk of sudden death.

Miocardiopatía hipertrófica. Estudio del gen de la troponina T en 127 familias españolas

Full English text available from: www.revespcardiol.org En esta ya clásica «Página del Editor» del mes de diciembre resumimos para nuestros lectores los datos de actividad y los principales resultados bibliométricos obtenidos por REVISTA ESPAÑOLA DE CARDIOLOGÍA en 2009. Además este año, de forma especial, añadimos algunas consideraciones generales sobre los logros conseguidos por la Revista en los últimos 6 años y unas reflexiones finales sobre nuestra política editorial1-11. Esta información fue presentada durante la reunión anual del Comité Editorial de la Revista en el seno del Congreso de las Enfermedades Cardiovasculares de la Sociedad Española de Cardiología (SEC) celebrado en Barcelona.

Mutación en homocigosis en el gen MYBPC3 asociada a fenotipos severos y alto riesgo de muerte súbita en una familia con miocardiopatía hipertrófica

El estudio genetico puede resultar una pieza clave en la evaluacion integral de la miocardiopatia hipertrofica familiar y en el desarrollo de una medicina individualizada. Hay pocos casos descritos, pero existe un grupo de pacientes con genotipos complejos asociados a manifestacion severa de la enfermedad y alto riesgo de muerte subita. Presentamos una familia caracterizada por evolucion precoz a disfuncion sistolica y diastolica en algunos de sus integrantes y muerte subita a edades tempranas en otros. Se detecto una mutacion en homocigosis (IVS6+5G>A) en el gen de la proteina C de union a la miosina, no descrita previamente, que nos permitio explicar el fenotipo de los afectados, estimar el riesgo en otros familiares y ofrecer consejo genetico.

A homozygous MYBPC3 gene mutation associated with a severe phenotype and a high risk of sudden death in a family with hypertrophic cardiomyopathy.

Genetic studies can play a key role in the comprehensive evaluation of familiar hypertrophic cardiomyopathy and in the development of individualized medicine. Although only a few cases have been described, there exists a group of patients with complex genotypes that are associated with severe disease manifestations and a high risk of sudden death. We describe a family in which some members experienced the early development of systolic and diastolic dysfunction while others experienced sudden death at a young age. We identified a novel homozygous mutation (IVS6+5G>A) in the myosin-binding protein-C gene that explained the phenotype of affected individuals and that enabled us to estimate the risk in other family members and to offer genetic counseling.

Trastornos graves de la conducción cardiaca e implante de marcapasos en pacientes con miocardiopatía hipertrófica

The aims of this study were to determine the prevalence of severe cardiac conduction disturbances in a cohort of 451 patients with hypertrophic cardiomyopathy and to describe the characteristics of, and outcomes in, those who required a permanent pacemaker. A pacemaker was implanted in 48 patients (11%): 20 had sinus node dysfunction and 28 had an atrioventricular conduction disturbance. Primary bradyarrhythmia (which was not related to iatrogenic atrioventricular block or therapeutic ablation of the atrioventricular node) was the reason for permanent pacemaker implantation in 36 patients (8%). In 18% of cases, at least one other family member had a permanent pacemaker. In this patient series, a high prevalence of severe cardiac conduction disturbance leading to permanent pacemaker implantation was observed. Severe cardiac conduction disturbance in hypertrophic cardiomyopathy may also have a familial component.

Avances en miocardiopatía dilatada idiopática: del genotipo al fenotipo clínico☆

La miocardiopatia dilatada idiopatica es una enfermedad familiar en un 30-50% de los casos. Hasta el momento se han identificado mutaciones asociadas con esta enfermedad en mas de 25 genes diferentes, relacionados con proteinas del citoesqueleto, el sarcomero, las uniones intercelulares, la membrana nuclear, los canales ionicos y las proteinas mitocondriales. Los estudios de correlacion entre genotipo y fenotipo muestran que ciertas caracteristicas clinicas, como la presencia de trastornos de la conduccion, miopatia esqueletica o hipertrabeculacion, pueden orientar hacia la causa genetica de la enfermedad. Por otra parte, mutaciones en los mismos genes pueden tener una expresion clinica muy variable y asociarse con diferentes fenotipos, como miocardiopatia hipertrofica, restrictiva, falta de compactacion, displasia arritmogenica del ventriculo derecho o miopatia esqueletica. Aunque los estudios geneticos no son una practica habitual en la miocardiopatia dilatada, disponemos ya de conocimientos y tecnologia suficiente para comenzar a utilizarlos. Para ello es esencial la colaboracion entre investigacion basica y clinica. Los medicos responsables del tratamiento de los pacientes con miocardiopatia dilatada deben aproximarse a la genetica y participar en la investigacion clinica con su propio conocimiento sobre la enfermedad. En esta revision intentamos proporcionar a los clinicos los conceptos fundamentales para conocer la situacion actual de la genetica de la miocardiopatia dilatada y comprender su utilidad, sus ventajas y sus limitaciones. La utilidad practica de la genetica es ya una realidad en las miocardiopatias y debemos hacer un esfuerzo para que los pacientes se beneficien del avance en el conocimiento.