Next-generation sequencing for diagnosis of thoracic aortic aneurysms and dissections: diagnostic yield, novel mutations and genotype phenotype correlations

Additional file 1. Complementary data on primer sequences, SKI amplification and survival analyses

Clinical Phenotypes and Prognosis of Dilated Cardiomyopathy Caused by Truncating Variants in the TTN Gene

BACKGROUND: Truncating variants in the TTN gene (TTNtv) are the commonest cause of heritable dilated cardiomyopathy. This study aimed to study the phenotypes and outcomes of TTNtv carriers. METHODS: Five hundred thirty-seven individuals (61% men; 317 probands) with TTNtv were recruited in 14 centers (372 [69%] with baseline left ventricular systolic dysfunction [LVSD]). Baseline and longitudinal clinical data were obtained. The primary end point was a composite of malignant ventricular arrhythmia and end-stage heart failure. The secondary end point was left ventricular reverse remodeling (left ventricular ejection fraction increase by ≥10% or normalization to ≥50%). RESULTS: Median follow-up was 49 (18-105) months. Men developed LVSD more frequently and earlier than women (45±14 versus 49±16 years, respectively; P=0.04). By final evaluation, 31%, 45%, and 56% had atrial fibrillation, frequent ventricular ectopy, and nonsustained ventricular tachycardia, respectively. Seventy-six (14.2%) individuals reached the primary end point (52 [68%] end-stage heart failure events, 24 [32%] malignant ventricular arrhythmia events). Malignant ventricular arrhythmia end points most commonly occurred in patients with severe LVSD. Male sex (hazard ratio, 1.89 [95% CI, 1.04-3.44]; P=0.04) and left ventricular ejection fraction (per 10% decrement from left ventricular ejection fraction, 50%; hazard ratio, 1.63 [95% CI, 1.30-2.04]; P<0.001) were independent predictors of the primary end point. Two hundred seven of 300 (69%) patients with LVSD had evidence of left ventricular reverse remodeling. In a subgroup of 29 of 74 (39%) patients with initial left ventricular reverse remodeling, there was a subsequent left ventricular ejection fraction decrement. TTNtv location was not associated with statistically significant differences in baseline clinical characteristics, left ventricular reverse remodeling, or outcomes on multivariable analysis (P=0.07). CONCLUSIONS: TTNtv is characterized by frequent arrhythmia, but malignant ventricular arrhythmias are most commonly associated with severe LVSD. Male sex and LVSD are independent predictors of outcomes. Mutation location does not impact clinical phenotype or outcomes

Association between Variants on Chromosome 4q25, 16q22 and 1q21 and Atrial Fibrillation in the Polish Population

Genome-wide studies have shown that polymorphisms on chromosome 4q25, 16q22 and 1q21 correlate with atrial fibrillation (AF). However, the distribution of these polymorphisms differs significantly among populations.To test the polymorphisms on chromosome 4q25, 16q22 and 1q21 in a group of patients (pts) that underwent catheter ablation of AF.Four hundred and ten patients with AF that underwent pulmonary vein isolation were included in the study. Control group (n = 550) was taken from healthy population, matched for age, sex and presence of hypertension. All participants were genotyped for the presence of the rs2200733, rs10033464, rs17570669, rs3853445, rs6838973 (4q25), rs7193343 (16q22) and rs13376333 (1q21) polymorphisms.All the polymorphisms tested (except rs17570669) correlated significantly with AF in univariate analysis (p values between 0.039 for rs7193343 and 2.7e-27 for rs2200733), with the odds ratio (OR) 0.572 and 0.617 for rs3853445 and rs6838973, respectively (protective role) and OR 1.268 to 3.52 for the other polymorphisms. All 4q25 SNPs tested but rs3853445 were independently linked with AF in multivariate logistic regression analysis. In haplotype analysis six out of nine 4q25 haplotypes were significantly linked with AF. The T allele of rs2200733 favoured increased number of episodes of AF per month (p = 0.045) and larger pulmonary vein diameter (recessive model, p = 0.032).Patients qualified for catheter ablation of AF have a significantly higher frequency of 4q25, 16q22 and 1q21 variants than the control group. The T allele of rs2200733 favours larger pulmonary veins and increased number of episodes of AF

Clinical phenotypes and prognosis of dilated cardiomyopathy caused by truncating variants in the TTN Gene.

Background: Truncating variants in the TTN gene (TTNtv) are the commonest cause of heritable dilated cardiomyopathy. This study aimed to study the phenotypes and outcomes of TTNtv carriers. Methods: Five hundred thirty-seven individuals (61% men; 317 probands) with TTNtv were recruited in 14 centers (372 [69%] with baseline left ventricular systolic dysfunction [LVSD]). Baseline and longitudinal clinical data were obtained. The primary end point was a composite of malignant ventricular arrhythmia and end-stage heart failure. The secondary end point was left ventricular reverse remodeling (left ventricular ejection fraction increase by ≥10% or normalization to ≥50%). Results: Median follow-up was 49 (18–105) months. Men developed LVSD more frequently and earlier than women (45±14 versus 49±16 years, respectively; P=0.04). By final evaluation, 31%, 45%, and 56% had atrial fibrillation, frequent ventricular ectopy, and nonsustained ventricular tachycardia, respectively. Seventy-six (14.2%) individuals reached the primary end point (52 [68%] end-stage heart failure events, 24 [32%] malignant ventricular arrhythmia events). Malignant ventricular arrhythmia end points most commonly occurred in patients with severe LVSD. Male sex (hazard ratio, 1.89 [95% CI, 1.04–3.44]; P=0.04) and left ventricular ejection fraction (per 10% decrement from left ventricular ejection fraction, 50%; hazard ratio, 1.63 [95% CI, 1.30–2.04]; P<0.001) were independent predictors of the primary end point. Two hundred seven of 300 (69%) patients with LVSD had evidence of left ventricular reverse remodeling. In a subgroup of 29 of 74 (39%) patients with initial left ventricular reverse remodeling, there was a subsequent left ventricular ejection fraction decrement. TTNtv location was not associated with statistically significant differences in baseline clinical characteristics, left ventricular reverse remodeling, or outcomes on multivariable analysis (P=0.07). Conclusions: TTNtv is characterized by frequent arrhythmia, but malignant ventricular arrhythmias are most commonly associated with severe LVSD. Male sex and LVSD are independent predictors of outcomes. Mutation location does not impact clinical phenotype or outcomes.pre-print1,66 M

BAG3-related myopathy, polyneuropathy and cardiomyopathy with long QT syndrome

10.1007/s10974-015-9431-3Journal of Muscle Research and Cell Motility366423-43

Titin Truncating Variants in Dilated Cardiomyopathy – Prevalence and Genotype-Phenotype Correlations

<div><p><i>TTN</i> gene truncating variants are common in dilated cardiomyopathy (DCM), although data on their clinical significance is still limited. We sought to examine the frequency of truncating variants in <i>TTN</i> in patients with DCM, including familial DCM (FDCM), and to look for genotype-phenotype correlations. Clinical cardiovascular data, family histories and blood samples were collected from 72 DCM probands, mean age of 34 years, 45.8% FDCM. DNA samples were examined by next generation sequencing (NGS) with a focus on the <i>TTN</i> gene. Truncating mutations were followed up by segregation study among family members. We identified 16 <i>TTN</i> truncating variants (<i>TTN</i> trunc) in 17 probands (23.6% of all cases, 30.3% of FDCM, 17.9% of sporadic DCM). During mean 63 months from diagnosis, there was no difference in adverse cardiac events between probands with and without TTN truncating mutations. Among relatives 29 mutation carriers were identified, nine were definitely affected (31%), eight probably affected (27.6%) one possibly affected (3.4%) and eleven were not affected (37.9%). When relatives with all affected statuses were combined, disease penetrance was still incomplete (62.1%) even after exclusion of unaffected relatives under 40 (82%) and was higher in males versus females. In all mutation carriers, during follow-up, 17.4% had major adverse cardiac events, and prognosis was significantly worse in men than in women. In conclusion, <i>TTN</i> truncating variants were observed in nearly one fourth of young DCM patient population, in vast majority without conduction system disease. Incomplete penetrance suggests possible influence of other genetic and/or environmental factors on the course of cardiotitinopathy. Counseling should take into account sex and incomplete penetrance.</p></div