Dataset Information

Genotype-Positive Status Is Associated With Poor Prognoses in Patients With Left Ventricular Noncompaction Cardiomyopathy.

ABSTRACT: Background Left ventricular noncompaction cardiomyopathy ( LVNC ) is a genetically and phenotypically heterogeneous disease. This study aims to investigate the genetic basis and genotype-phenotype correlations in a cohort of Chinese patients with LVNC . Methods and Results A total of 72 cardiomyopathy-associated genes were comprehensively screened in 83 adults and 17 children with LVNC by targeted sequencing. Pathogenicity of the detected variants was determined according to their prevalence and American College of Medical Genetics and Genomics recommendations. Baseline and follow-up clinical data were collected. The primary end point was a composite of death and heart transplantation. Overall, 42 pathogenic variants were identified in 38 patients (38%), with TTN , MYH 7, MYBPC 3, and DSP being the most commonly involved genes. At baseline, genotype-positive adults had higher rates of atrial fibrillation and family history, and lower left ventricular ejection fraction, compared with genotype-negative adults. During a median follow-up of 4.2 years, more primary end points occurred in genotype-positive adults than in genotype-negative adults (50.0% versus 23.5%; P=0.013). Multivariable analysis demonstrated that genotype-positive status was associated with higher risks of death and heart transplantation, independent of age, sex, and cardiac function at baseline in patients with LVNC (adjusted hazards ratio, 2.49; 95% confidence interval, 1.15-5.37; P=0.020). Conclusions Our study revealed a distinct genetic spectrum in Chinese patients with LVNC , with variants in TTN , MYH 7, MYBPC 3, and DSP being the most common. The presence of pathogenic variants is an independent risk factor for adverse outcomes and may aid in risk stratification in adult patients. Larger studies are needed to confirm these findings.

SUBMITTER: Li S

PROVIDER: S-EPMC6474962 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genotype-Positive Status Is Associated With Poor Prognoses in Patients With Left Ventricular Noncompaction Cardiomyopathy.

Li Shijie S Zhang Ce C Liu Nana N Bai Hui H Hou Cuihong C Wang Jizheng J Song Lei L Pu Jielin J

Journal of the American Heart Association 20181001 20

Background Left ventricular noncompaction cardiomyopathy ( LVNC ) is a genetically and phenotypically heterogeneous disease. This study aims to investigate the genetic basis and genotype-phenotype correlations in a cohort of Chinese patients with LVNC . Methods and Results A total of 72 cardiomyopathy-associated genes were comprehensively screened in 83 adults and 17 children with LVNC by targeted sequencing. Pathogenicity of the detected variants was determined according to their prevalence and ...[more]

PMID: 30371277

Similar Datasets

Project description:BackgroundLess than 40% of patients with dilated cardiomyopathy (DCM) have a pathogenic/likely pathogenic genetic variant identified. TBX20 has been linked to congenital heart defects; although an association with left ventricular noncompaction (LVNC) and DCM has been proposed, it is still considered a gene with limited evidence for these phenotypes. This study sought to investigate the association between the TBX20 truncating variant (TBX20tv) and DCM/LVNC.MethodsTBX20 was sequenced by next-generation sequencing in 7463 unrelated probands with a diagnosis of DCM or LVNC, 22 773 probands of an internal comparison group (hypertrophic cardiomyopathy, channelopathies, or aortic diseases), and 124 098 external controls (individuals from the gnomAD database). Enrichment of TBX20tv in DCM/LVNC was calculated, cosegregation was determined in selected families, and clinical characteristics and outcomes were analyzed in carriers.ResultsTBX20tv was enriched in DCM/LVNC (24/7463; 0.32%) compared with internal (1/22 773; 0.004%) and external comparison groups (4/124 098; 0.003%), with odds ratios of 73.23 (95% CI, 9.90-541.45; P<0.0001) and 99.76 (95% CI, 34.60-287.62; P<0.0001), respectively. TBX20tv was cosegregated with DCM/LVNC phenotype in 21 families for a combined logarythm of the odds score of 4.53 (strong linkage). Among 57 individuals with TBX20tv (49.1% men; mean age, 35.9±20.8 years), 41 (71.9%) exhibited DCM/LVNC, of whom 14 (34.1%) had also congenital heart defects. After a median follow-up of 6.9 (95% CI, 25-75:3.6-14.5) years, 9.7% of patients with DCM/LVNC had end-stage heart failure events and 4.8% experienced malignant ventricular arrhythmias.ConclusionsTBX20tv is associated with DCM/LVNC; congenital heart defect is also present in around one-third of cases. TBX20tv-associated DCM/LVNC is characterized by a nonaggressive phenotype, with a low incidence of major cardiovascular events. TBX20 should be considered a definitive gene for DCM and LVNC and routinely included in genetic testing panels for these phenotypes.

Project description:BackgroundLeft ventricular noncompaction cardiomyopathy (LVNC) is a rare cardiac disorder characterised by the presence of a two-layer myocardium with prominent ventricular trabeculation, intertrabecular deep depressions and an increased risk of heart failure, atrial and ventricular arrhythmias and systemic thromboembolic events in affected patients. The heterogeneous molecular aetiology solved in 10%-50% of patients more frequently involves sarcomeric, cytoskeletal or ion channel protein dysfunction-mainly related to causative MYH7, TTN or MYBPC3 variants. The aim of the study was to determine the molecular spectrum of isolated LVNC in a group of children examined in a single paediatric reference centre.MethodsThirty-one paediatric patients prospectively diagnosed with LVNC by echocardiography and cardiovascular magnetic resonance examination were recruited into the study group. The molecular analysis included next-generation sequencing (gene panel or whole exome) and classic Sanger sequencing. All selected variants with high priority were co-segregated in the available parents.ResultsWe identified 16 distinct variants in 11 genes in 16 patients (52%), including 10 novel alterations. The most frequent defects in our cohort were found in the genes HCN4 (n = 4), MYH7 (n = 2) and PRDM16 (n = 2). Other likely disease-causing variants were detected in ACTC1, ACTN2, HCCS, LAMA4, MYH6, RBM20, TAFFAZIN and TTN. Patients with established molecular defects more often presented with arrhythmia, thromboembolic events and death, whereas the predominant symptoms in patients with no identified molecular defects were heart failure and the presence of late gadolinium enhancement.ConclusionThis study expands the genetic and clinical spectrum of childhood LVNC. Although the molecular aetiology of LVNC varies widely, the comprehensive testing of a wide panel of cardiomyopathy-related genes helped to identify underlying molecular defects in more than half of the children in the study group. The molecular spectrum in our cohort correlated with the occurrence of arrhythmia, death and a family history of cardiomyopathy. We confirmed that genetic testing is an integral part of the work-up and management LVNC in children.

Dataset Information

Genotype-Positive Status Is Associated With Poor Prognoses in Patients With Left Ventricular Noncompaction Cardiomyopathy.

Publications

Genotype-Positive Status Is Associated With Poor Prognoses in Patients With Left Ventricular Noncompaction Cardiomyopathy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets