[Mutations in sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in patients with hypertrophic cardiomyopathy]. / Espectro mutacional de los genes sarcoméricos MYH7, MYBPC3, TNNT2, TNNI3 y TPM1 en pacientes con miocardiopatía hipertrófica.

INTRODUCTION AND OBJECTIVES: Mutation of a sarcomeric gene is the most frequent cause of hypertrophic cardiomyopathy. For each such gene, however, previous studies have reported a range of different mutation frequencies, and clinical manifestations have been highly heterogeneous, both of which limit the use of genetic information in clinical practice. Our aim was to determine the frequency of mutations in the sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in a cohort of Spanish patients with hypertrophic cardiomyopathy. METHODS: We used sequencing to analyze the coding regions of these five genes in 120 patients (29% with a family history) and investigated how the patient phenotype varied with the gene mutated. RESULTS: In total, 32 patients were found to have mutations: 10 in MYH7 (8%), 20 in MYBPC3 (16%), 2 in TNNT2, 1 in TPM1 and none in TNNI3. Overall, 61% of mutations had not been described before. Two patients had two mutations (i.e., double mutants). There was no difference in the mean age at diagnosis or the extent of the hypertrophy between those with MYH7 mutations and those with MYBPC3 mutations. CONCLUSIONS: Some 26% of patients had a mutation in one of the five sarcomeric genes investigated. More than half of the mutations had not been described before. The MYBPC3 gene was the most frequently mutated, followed by MYH7. No phenotypic differences were observed between carriers of the various mutations, which makes it difficult to use genetic information to stratify risk in these patients.

Espectro mutacional de los genes sarcoméricos MYH7, MYBPC3, TNNT2, TNNI3 y TPM1 en pacientes con miocardiopatía hipertrófica / Mutations in sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in patients with hypertrophic cardiomyopathy

Introducción y objetivos. Desarrollar un análisis coste-efectividad de un programa de cribado genético de familares de primer grado de pacientes con hipercolesterolemia familiar (HF), seguido de tratamiento cuando fuera necesario, frente a la alternativa de no cribar. Métodos. Se realiza un análisis coste-efectividad en el cual se modeló el efecto del tratamiento con estatinas en personas diagnosticadas de HF tras el cribado genético. La incertidumbre se trató mediante análisis de sensibilidad univariable y probabilístico. La estrategia alternativa considerada es no cribar. El análisis coste-efectividad considera como resultado sobre la salud los años de vida ganados (AVG) e incluye los costes del cribado, tratamiento con estatinas, visitas al especialista y hospitalizaciones. Asimismo, se calculó el valor esperado de la información perfecta, como complemento del análisis de sensibilidad. Resultados. En el caso base, el coste incremental por AVG del programa de cribado a pacientes directos asciende a 3.423 euros/AVG. Los resultados varían en el análisis de sensibilidad, pero las conclusiones son robustas frente a cambios en los parámetros considerados. El programa de cribado es óptimo frente a la alternativa considerada, con un 95% de probabilidad si la disposición a pagar, social o del decisor sanitario, fuera de al menos 7.400 euros/AVG. Conclusiones. El análisis señala que el programa de cribado genético más tratamiento en familiares directos de personas con HF presenta una buena relación incremental de coste-efectividad frente a la alternativa de no cribar (AU)

Introduction and objectives. The aim was to assess the cost-effectiveness of a genetic screening program for first-degree relatives of patients with familial hypercholesterolemia (FH), followed by treatment when necessary, compared with the alternative of no screening. Methods. The cost-effectiveness analysis modeled the effect of statin treatment on individuals who were diagnosed with FH after genetic screening. The impact of uncertainty was evaluated using univariate probabilistic sensitivity analysis. The alternate strategy considered was no screening. In the cost-effectiveness analysis, the number of life-years gained (LYG) was regarded as the health outcome and the costs of screening, statin treatment, specialist consultations and hospital visits were all included. In addition, the expected value of perfect information was calculated as part of the sensitivity analysis. Results. In the base case, the incremental cost of the screening program for close relatives was 3423 euros per LYG. Although the sensitivity analysis gave a range of results, the conclusions were not affected by changes in the parameters considered. The screening program was found to be better than the alternative considered at a probability level of 95% if the acceptable level of health-care costs was at least 7400 euros per LYG. Conclusions. This analysis indicates that a genetic screening program, supplemented by treatment, for the close relatives of individuals with FH is preferable to the alternative of no screening in terms of incremental cost-effectiveness (AU)

Prevalence and spectrum of mutations in the sarcomeric troponin T and I genes in a cohort of Spanish cardiac hypertrophy patients.

We sequenced the coding exons of the cardiac troponins T (TNNT2) and I (TNNI3) genes in 115 Spanish HCM-patients (32% with a family history of the disease). Only two (2%) had mutations in the TNNT2 (Arg278>Cys and Arg92>Lys). These mutations were associated with variable clinical outcomes. No patient had TNNI3-mutation. We also genotyped these patients and 320 healthy controls for a 5 bp insertion/deletion (I/D) polymorphism in intron 3 of TNNT2. DD-homozygotes for the 5 bp I/D polymorphism were significantly more frequent among the patients (OR=1.83, 95% CI=2.10-5.16).