Cardiomyopathies are a heterogeneous group of primary diseases of the myocardium, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular ...cardiomyopathy (ARVC), with higher morbidity and mortality. These diseases are genetically diverse and associated with rare mutations in a large number of genes, many of which overlap among the phenotypes. To better investigate the genetic overlap between these three phenotypes and to identify new genotype-phenotype correlations, we designed a custom gene panel consisting of 115 genes known to be associated with cardiomyopathic phenotypes and channelopathies. A cohort of 38 unrelated patients, 16 affected by DCM, 14 by HCM and 8 by ARVC, was recruited for the study on the basis of more severe phenotypes and family history of cardiomyopathy and/or sudden death. We detected a total of 142 rare variants in 40 genes, and all patients were found to be carriers of at least one rare variant. Twenty-eight of the 142 rare variants were also predicted as potentially pathogenic variants and found in 26 patients. In 23 out of 38 patients, we found at least one novel potential gene-phenotype association. In particular, we detected three variants in OBSCN gene in ARVC patients, four variants in ANK2 gene and two variants in DLG1, TRPM4, and AKAP9 genes in DCM patients, two variants in PSEN2 gene and four variants in AKAP9 gene in HCM patients. Overall, our results confirmed that cardiomyopathic patients could carry multiple rare gene variants; in addition, our investigation of the genetic overlap among cardiomyopathies revealed new gene-phenotype associations. Furthermore, as our study confirms, data obtained using targeted next-generation sequencing could provide a remarkable contribution to the molecular diagnosis of cardiomyopathies, early identification of patients at risk for arrhythmia development, and better clinical management of cardiomyopathic patients.
Mutations in the lamin A/C gene (LMNA) were associated with dilated cardiomyopathy (DCM) and, recently, were related to severe forms of arrhythmogenic right ventricular cardiomyopathy (ARVC). Both ...genetic and phenotypic overlap between DCM and ARVC was observed; molecular pathomechanisms leading to the cardiac phenotypes caused by LMNA mutations are not yet fully elucidated. This study involved a large Italian family, spanning 4 generations, with arrhythmogenic cardiomyopathy of different phenotypes, including ARVC, DCM, system conduction defects, ventricular arrhythmias, and sudden cardiac death. Mutation screening of LMNA and ARVC-related genes PKP2, DSP, DSG2, DSC2, JUP, and CTNNA3 was performed. We identified a novel heterozygous mutation (c.418_438dup) in LMNA gene exon 2, occurring in a highly conserved protein domain across several species. This newly identified variant was not found in 250 ethnically-matched control subjects. Genotype-phenotype correlation studies suggested a co-segregation of the LMNA mutation with the disease phenotype and an incomplete and age-related penetrance. Based on clinical, pedigree, and molecular genetic data, this mutation was considered likely disease-causing. To clarify its potential pathophysiologic impact, functional characterization of this LMNA mutant was performed in cultured cardiomyocytes expressing EGFP-tagged wild-type and mutated LMNA constructs, and indicated an increased nuclear envelope fragility, leading to stress-induced apoptosis as the main pathogenetic mechanism. This study further expands the role of the LMNA gene in the pathogenesis of cardiac laminopathies, suggesting that LMNA should be included in mutation screening of patients with suspected arrhythmogenic cardiomyopathy, particularly when they have ECG evidence for conduction defects. The combination of clinical, genetic, and functional data contribute insights into the pathogenesis of this form of life-threatening arrhythmogenic cardiac laminopathy.
Arrhythmic risk stratification in patients with Lamin A/C gene (LMNA)-related cardiomyopathy influences clinical decisions. An implantable cardioverter defibrillator (ICD) should be considered in ...patients with an estimated 5-year risk of malignant ventricular arrhythmia (MVA) of ≥10%. The risk prediction score for MVA includes non-missense LMNA mutations, despite their role as an established risk factor for sudden cardiac death (SCD) has been questioned in several studies. The purpose of this study is to investigate cardiac features and find gene–phenotype correlations that would contribute to the evidence on the prognostic implications of non-missense vs. missense mutations in a cohort of LMNA mutant patients. An observational, prospective study was conducted in which 54 patients positive for a Lamin A/C mutation were enrolled, and 20 probands (37%) were included. The median age at first clinical manifestation was 41 (IQR 19) years. The median follow-up was 8 years (IQR 8). The type of LMNA gene mutation was distributed as follows: missense in 26 patients (48%), non-frameshift insertions in 16 (30%), frameshift deletions in 5 (9%), and nonsense in 7 (13%). Among the missense mutation carriers, two (8%) died and four (15%) were admitted onto the heart transplant list or underwent transplantation, with a major adverse cardiovascular event (MACE) rate of 35%. No statistically significant differences in MACE prevalence were identified according to the missense and non-missense mutation groups (p value = 0.847). Our data shift the spotlight on this considerable topic and could suggest that some missense mutations may deserve attention regarding SCD risk stratification in real-world clinical settings.
Ventricular Repolarization Dynamicity Provides Independent Prognostic Information Toward Major Arrhythmic Events in Patients With Idiopathic Dilated Cardiomyopathy Massimo Iacoviello, Cinzia Forleo, ...Pietro Guida, Roberta Romito, Antonio Sorgente, Sandro Sorrentino, Silvana Catucci, Filippo Mastropasqua, Mariavittoria Pitzalis We evaluated whether the analysis of ventricular repolarization dynamicity by calculating the slope of linear regression analysis of QT and RR intervals was associated with an increased arrhythmic risk in a group of patients with idiopathic dilated cardiomyopathy (DCM). Both univariate and multivariate analysis showed that QT dynamicity, nonsustained ventricular tachycardia, and left ventricular ejection fraction were independently associated with arrhythmic events. These results suggest a possible clinical usefulness of QT dynamicity analysis in stratifying arrhythmic risk in DCM patients.
Abstract Although the pathophysiology of vasovagal syncope is not completely understood, the involvement of sympathetic nervous system alterations has been suggested. Since predisposition to fainting ...during orthostatic challenge may be associated with genetic variations, we sought to explore the role of genetic polymorphisms affecting sympathetic nervous system function in the susceptibility to tilt-induced vasovagal syncope. We genotyped 129 subjects with recurrent unexplained syncope who underwent tilt testing, and investigated the recurrence of syncope. The analysed polymorphisms were Arg492Cys ( ADRA1A gene), Ser49Gly and Arg389Gly ( ADRB1 ), Arg16Gly and Gln27Glu ( ADRB2 ), 825C/T ( GNB3 ), –1021C/T ( DBH ) and S/L ( SLC6A4 ). No association of the aforementioned genetic variants with both tilt test outcomes and new syncopal episodes during follow-up was found. None of the considered polymorphisms influencing sympathetic activity is a major risk factor for vasovagal syncope in Italian patients.
Abstract Background Idiopathic dilated cardiomyopathy (IDC) has multiple genetic and acquired causes. Apelin is an endogenous peptide that increases cardiac inotropism through his APJ receptor. No ...data are available concerning the APJ gene mutations responsible for IDC or on the role of APJ receptor gene variants in predicting heart failure (HF) progression. Methods and Results We prospectively evaluated 202 consecutive patients with IDC and 202 matched controls: 90 were screened for APJ gene mutations and all 202 were genotyped for G212A and A445C APJ receptor polymorphisms. No mutations were found within the coding or untranslated regions of the APJ receptor, and no differences in allelic or genotype frequencies were observed comparing patients with a healthy control population. The correlations between APJ receptor polymorphisms and HF progression were assessed. During a median follow-up of 37 months, 35 patients experienced HF progression. Univariate analysis showed that patients carrying at least 1 copy of 212A had a significantly lower risk for HF-related events than those who were homozygous for the G212 variant, and multivariate analysis confirmed that it was significantly related to a more favorable prognosis. Conclusions APJ is unlikely to be a gene causing IDC, but the independent correlation between the 212A allele and a better prognosis suggests that it might act as a modifier gene.
Abstract
Motivation
Clinical applications of genome re-sequencing technologies typically generate large amounts of data that need to be carefully annotated and interpreted to identify genetic ...variants potentially associated with pathological conditions. In this context, accurate and reproducible methods for the functional annotation and prioritization of genetic variants are of fundamental importance.
Results
In this article, we present VINYL, a flexible and fully automated system for the functional annotation and prioritization of genetic variants. Extensive analyses of both real and simulated datasets suggest that VINYL can identify clinically relevant genetic variants in a more accurate manner compared to equivalent state of the art methods, allowing a more rapid and effective prioritization of genetic variants in different experimental settings. As such we believe that VINYL can establish itself as a valuable tool to assist healthcare operators and researchers in clinical genomics investigations.
Availability and implementation
VINYL is available at http://beaconlab.it/VINYL and https://github.com/matteo14c/VINYL.
Supplementary information
Supplementary data are available at Bioinformatics online.
Abstract Background A systematic evaluation focused on sensitivity and specificity of head-up tilt testing (HUT) for diagnosing vasovagal syncope has not been previously performed. We conducted a ...meta-analysis of studies comparing HUT outcome between patients with syncope of unknown origin and control subjects without previous syncope. Methods We searched Pubmed and Embase databases for all English-only articles concerning case-control studies estimating the diagnostic yield of HUT, and selected 55 articles, published before March 2012, including 4361 patients and 1791 controls. The influence of age, test duration, tilt angle, and nitroglycerine or isoproterenol stimulation on tilt testing outcome was analyzed. Results Head-up tilt testing demonstrated to have a good overall ability to discriminate between symptomatic patients and asymptomatic controls with an area under the summary receiver-operating characteristics curve of 0.84 and an adjusted diagnostic odds ratio of 12.15 (p < 0.001). A significant inverse relationship between sensitivity and specificity of tilt testing for each study was observed (p < 0.001). At multivariate analysis, advancing age and a 60° tilt angle showed a significant effect in reducing sensitivity and increasing specificity of the test. Nitroglycerine significantly raised tilt testing sensitivity by maintaining a similar specificity in comparison to isoproterenol. Conclusions The results from this meta-analysis show the high overall performance of HUT for diagnosing vasovagal syncope. Our findings provide useful information for evaluating clinical and instrumental parameters together with pharmacological stressors influencing HUT accuracy. This could allow the drawing of tilt testing protocols tailored on the diagnostic needs of each patient with unexplained syncope.
Brugada syndrome is associated with a high risk of sudden cardiac death and is caused by mutations in the cardiac voltage-gated sodium channel gene. Previously, the R282H-SCN5A mutation in the sodium ...channel gene was identified in patients with Brugada syndrome. In a family carrying the R282H-SCN5A mutation, an asymptomatic individual had a common H558R-SCN5A polymorphism and the mutation on separate chromosomes. Therefore, we hypothesized that the polymorphism could rescue the mutation.
In heterologous cells, expression of the mutation alone did not produce sodium current. However, coexpressing the mutation with the polymorphism produced significantly greater current than coexpressing the mutant with the wild-type gene, demonstrating that the polymorphism rescues the mutation. Using immunocytochemistry, we demonstrated that the R282H-SCN5A construct can traffic to the cell membrane only in the presence of the H558R-SCN5A polymorphism. Using fluorescence resonance energy transfer and protein fragments centered on H558R-SCN5A, we demonstrated that cardiac sodium channels preferentially interact when the polymorphism is expressed on one protein but not the other.
This study suggests a mechanism whereby the Brugada syndrome has incomplete penetrance. More importantly, this study suggests that genetic polymorphisms may be a potential target for future therapies aimed at rescuing specific dysfunctional protein channels.
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