TTN 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 TTN 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 TTN gene. Truncating mutations were followed up by segregation study among family members. We identified 16 TTN truncating variants (TTN 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, TTN 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.

BackgroundThoracic aortic aneurysms and dissections (TAAD) are silent but possibly lethal condition with up to 40 % of cases being hereditary. Genetic background is heterogeneous. Recently next-generation sequencing enabled efficient and cost-effective examination of gene panels. Aim of the study was to define the diagnostic yield of NGS in the 51 TAAD patients and to look for genotype–phenotype correlations within families of the patients with TAAD.Methods51 unrelated TAAD patients were examined by either whole exome sequencing or TruSight One sequencing panel. We analyzed rare variants in 10 established thoracic aortic aneurysms-associated genes. Whenever possible, we looked for co-segregation in the families. Kaplan–Meier survival curve was constructed to compare the event-free survival depending on genotype. Aortic events were defined as acute aortic dissection or first planned aortic surgery.Results and discussionIn 21 TAAD patients we found 22 rare variants, 6 (27.3 %) of these were previously reported, and 16 (73.7 %) were novel. Based on segregation data, functional analysis and software estimations we assumed that three of novel variants were causative, nine likely causative. Remaining four were classified as of unknown significance (2) and likely benign (2). In all, 9 (17.6 %) of 51 probands had a positive result when considering variants classified as causative only and 18 (35.3 %) if likely causative were also included. Genotype-positive probands (n = 18) showed shorter mean event free survival (41 years, CI 35–46) than reference group, i.e. those (n = 29) without any plausible variant identified (51 years, CI 45–57, p = 0.0083). This effect was also found when the ‘genotype-positive’ group was restricted to probands with ‘likely causative’ variants (p = 0.0092) which further supports pathogenicity of these variants. The mean event free survival was particularly low (37 years, CI 27–47) among the probands with defects in the TGF beta signaling (p = 0.0033 vs. the reference group).ConclusionsThis study broadens the spectrum of genetic background of thoracic aneurysms and dissections and supports its potential role as a prognostic factor in the patients with the disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0870-4) contains supplementary material, which is available to authorized users.

IMPORTANCETruncating variants in the gene encoding filamin C (FLNCtv) are associated with arrhythmogenic and dilated cardiomyopathies with a reportedly high risk of ventricular arrhythmia.OBJECTIVE To determine the frequency of and risk factors associated with adverse events among FLNCtv carriers compared with individuals carrying TTN truncating variants (TTNtv). DESIGN, SETTING, AND PARTICIPANTSThis cohort study recruited 167 consecutive FLNCtv carriers and a control cohort of 244 patients with TTNtv matched for left ventricular ejection fraction (LVEF) from 19 European cardiomyopathy referral units between 1990 and 2018. Data analyses were conducted between June and October, 2020. MAIN OUTCOMES AND MEASURESThe primary end point was a composite of malignant ventricular arrhythmia (MVA) (sudden cardiac death, aborted sudden cardiac death, appropriate implantable cardioverter-defibrillator shock, and sustained ventricular tachycardia) and end-stage heart failure (heart transplant or mortality associated with end-stage heart failure). The secondary end point comprised MVA events only. RESULTSIn total, 167 patients with FLNCtv were studied (55 probands [33%]; 89 men [53%]; mean [SD] age at baseline evaluation, 43 [18] years). For a median follow-up of 20 months (interquartile range, 7-60 months), 29 patients (17.4%) reached the primary end point (19 patients with MVA and 10 patients with end-stage heart failure). Eight (44%) arrhythmic events occurred among individuals with baseline mild to moderate left ventricular systolic dysfunction (LVSD) (LVEF = 36%-49%). Univariable risk factors associated with the primary end point included proband status, LVEF decrement per 10%, ventricular ectopy (Ն500 in 24 hours) and myocardial fibrosis detected on cardiac magnetic resonance imaging. The LVEF decrement (hazard ratio [HR] per 10%, 1.83 [95% CI, 1.30-2.57]; P < .001) and proband status (HR, 3.18 [95% CI, 1.12-9.04]; P = .03) remained independent risk factors on multivariable analysis (excluding myocardial fibrosis and ventricular ectopy owing to case censoring). There was no difference in freedom from MVA between FLNCtv carriers with mild to moderate or severe (LVEF Յ35%) LVSD (HR, 1.29 [95% CI,]; P = .64). Carriers of FLNCtv with impaired LVEF at baseline evaluation (n = 69) had reduced freedom from MVA compared with 244 TTNtv carriers with similar baseline LVEF (for mild to moderate LVSD: HR, 16.41 [95% CI,]; P < .001; for severe LVSD: HR, 2.47 [95% CI, 1.04-5.87]; P = .03). CONCLUSIONS AND RELEVANCEThe high frequency of MVA among patients with FLNCtv with mild to moderate LVSD suggests that higher LVEF values than those currently recommended should be considered for prophylactic implantable cardioverter-defibrillator therapy in FLNCtv carriers.

BackgroundMutations of the SCN5A gene are reported in 2-4% of patients with dilated cardiomyopathy (DCM). In such cases, DCM is associated with different rhythm disturbances such as the multifocal ectopic Purkinje-related premature contractions and atrial fibrillation. Arrhythmia often occurs at a young age and is the first symptom of heart disease.Case presentationWe present the case of 55-year old male with a 30-year history of heart failure (HF) in the course of familial DCM and complex ventricular tachyarrhythmias, which constituted 50-80% of the whole rhythm. The patient was qualified for heart transplantation because of the increasing symptoms of HF. We revealed the heterozygotic R222Q mutation in SCN5A by means of whole exome sequencing. After the quinidine treatment, a rapid and significant reduction of ventricular tachyarrhythmias and an improvement in the myocardial function were observed and this effect remained constant in the 2.5-year follow-up. This effect was observed even in the presence of concomitant coronary artery disease.ConclusionsPatients with familial DCM and Purkinje-related ventricular arrhythmias should be offered genetic screening. The quinidine treatment for the SCN5A R222Q mutation can be life saving for patients.