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

<p>With 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.</p><p>We 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 1.43.0). 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.</p><p>The 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.</p>

Gender-specific differences in major cardiac events and mortality in lamin A/C mutation carriers

<p>Mutations in the lamin A/C gene (LMNA) cause a variety of clinical phenotypes, including dilated cardiomyopathy. LMNA is one of the most prevalent mutated genes in dilated cardiomyopathy, and is associated with a high risk of arrhythmias, sudden cardiac death, and heart failure. There are few data on the impact of age and gender on cardiac disease penetrance and mortality.</p><p>In a multicentre cohort of 269 LMNA mutation carriers, we evaluated gender-specific penetrance of cardiac involvement and major cardiac events. All-cause mortality of mutation carriers [standardized mortality ratio (SMR)] was determined. Cardiac disease penetrance was age dependent and almost complete at the age of 70 years. The presence of an LVEF 45 was significantly higher in men (P 0.001). However, there was no difference between genders in the prevalence of atrioventricular block, atrial tachyarrhythmias, and non-sustained ventricular tachycardia. Malignant ventricular arrhythmias (26 vs. 8) and end-stage heart failure (28 vs. 14) were more common in men than in women (P 0.001 and P 0.006, respectively). All-cause mortality of mutation carriers was significantly increased [SMR 4.0, 95 confidence interval (CI) 2.85.2] between the ages of 15 and 75 years. Mortality in men was higher than in women (hazard ratio 2.2, 95 CI 1.24.3).</p><p>This large cohort of LMNA mutation carriers demonstrates a high cardiac disease penetrance and a high mortality in mutation carriers. Male mutation carriers have a worse prognosis due to a higher prevalence of malignant ventricular arrhythmias and end-stage heart failure.</p>