Genetic analysis in 418 index patients with idiopathic dilated cardiomyopathy: overview of 10 years' experience

Abstract

AimsWith more than 40 dilated cardiomyopathy (DCM)-related genes known, genetic analysis of patients with idiopathic DCM is costly and time-consuming. We describe the yield from genetic analysis in DCM patients in a large Dutch cohort. Methods and resultsWe collected cardiological and neurological evaluations, family screenings, and genetic analyses for 418 index patients with idiopathic DCM. We identified 35 (putative) pathogenic mutations in 82 index patients (20%). The type of DCM influenced the yield, with mutations found in 25% of familial DCM cases, compared with 8% of sporadic DCM cases and 62% of cases where DCM was accompanied by neuromuscular disease. A PLN founder mutation (43 cases) and LMNA mutations (19 cases, 16 different mutations) were most prevalent and often demonstrated a specific phenotype. Other mutations were found in: MYH7, DES, TNNT2, DMD, TPM1, DMPK, SCN5A, SGCB (homozygous), and TNNI3. After a median follow-up of 40 months, the combined outcome of death from any cause, heart transplantation, or malignant ventricular arrhythmias in patients with a mutation was worse than in those without an identified mutation (hazard ratio 2.0, 95% confidence interval 1.4 -3.0). This seems to be mainly attributable to a high prevalence of malignant ventricular arrhythmias and end-stage heart failure in LMNA and PLN mutation carriers. ConclusionThe yield of identified mutations in DCM index patients with clinical clues, such as associated neuromuscular disease or familial occurrence, is higher compared with those without these clues. For sporadic DCM, specific clinical characteristics may be used to select cases for DNA analysis.--

Yield of Molecular and Clinical Testing for Arrhythmia Syndromes

“…These percentages compare equally well with published series: 38% to 52% in HCM 11,13 (smaller cohorts) and 20% in dilated cardiomyopathy (larger cohort that included patients from the present study). 12 We also analyzed the yield in familial or isolated cases separately. The yield was higher in familial cases with primary electric diseases than in isolated cases and also tended to be higher in familial cases with cardiomyopathies.…”

“…The published yield of molecular testing differs between the various diseases, ranging from 20% (Brugada syndrome [BrS]) to 65% (long-QT syndrome [LQTS]) in primary electric diseases and from 20% to 52% in cardiomyopathies. [8][9][10][11][12][13] Accordingly, there is widespread growing interest in investing in cardiogenetic care and an increasing need to establish the yield of cardiogenetic care.…”

The role of genetic testing in unexplained sudden death

“…98 Mutations in .30 genes have been associated with DCM, most following an autosomal dominant inheritance pattern. 99 The titin gene (TTN) probably accounts for approximately 20% of cases in recent studies but the high frequency of rare variants has limited the clinical utility of assessing risk; other genes have a low yield. 100 Extensive or targeted (LMNA and SCN5A) testing is recommended (class I indication) for those patients with significant conduction disease with or without overt DCM as mutations in these genes can indicate an increased risk of SCD.…”

Follow-up care by a genetic counsellor for relatives at risk for cardiomyopathies is cost-saving and well-appreciated: a randomised comparison

“…They were carriers of variants that affect function in the LMNA, DES or PLN genes, who are at a higher prior risk for malignant ventricular arrhythmias compared with the other groups. 9,10 They were phenotype-negative relatives of index patients with potentially inherited DCM or HCM in whom no variant that affects function had been identified. All participants had been counselled at the Department of Genetics, UMCG.…”