Abstract 18381: Ten Years Genetic Screening in a Large Cohort of Patients with Dilated Cardiomyopathy
Introduction: Idiopathic Dilated Cardiomyopathy (DCM) is familial in up to 35% of cases. Conventional genetic analysis of DCM is hampered by genetic heterogeneity because over 40 DCM related genes have been identified, most of them accounting for only a minority of cases. We hypothesized that conventional genetic screening in DCM index-patients lead to a modest mutational yield. Therefore we evaluated the results of genetic screening in DCM patients over the last 10 years.
Methods: Clinical data, family history, and results of conventional genetic analyses in 418 DCM index-patients (224 familial, 173 sporadic and 21 with neuromuscular disease) were collected. We assessed the prevalence of mutations in DCM related genes and evaluated its clinical expression.
Results: Thirty-five putative pathogenic mutations were identified in 82 of 418 DCM index-patients (20%). When analyzing subgroups, mutations were found in 25% of familial DCM, 8% of sporadic DCM, and 62% of patients with DCM and neuromuscular disease. Most prevalent were a PLN founder mutation (p.R14del) in 43 index-patients and 16 different LMNA mutations in 19 index-patients. The majority of these patients showed a gene-specific phenotype. Other genes involved were: MYH7, DES, TNNT2, DMD, TPM1, DMPK, SCN5A, SCGB, and TNNI3. Only one patient was double heterozygous. After a median follow-up of 40 months (interquartile range; 13 to 90 months), combined death from any cause, cardiac transplantation, and malignant ventricular arrhythmias in mutation carriers was worse compared to DCM patients without a known genetic cause (HR 2.0, 95% CI: 1.4-3.0). This seems to be mainly due to the arrhythmogenic phenotypes of LMNA and PLN mutation carriers.
Conclusions: Extensive genetic analysis in a large and well-defined DCM cohort shows that the yield of genetic analysis is high (62%) in DCM patients with neuromuscular disease, moderate (25%) in familial DCM, and low (8%) in sporadic DCM. When resources are limited, specific clinical characteristics can be used to select cases for DNA analysis. These results form a solid base to develop next generation sequencing for DCM that will provide high-throughput, rapid and affordable genetic analysis for DCM.
- © 2012 by American Heart Association, Inc.