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Clinical implications of sarcomere and nonsarcomere gene variants in patients with left ventricular noncompaction cardiomyopathy.

ABSTRACT: BACKGROUND:Robust data regarding genotype-phenotype correlations in left ventricular noncompaction cardiomyopathy (LVNC) are lacking. METHODS:About 72 cardiomyopathy-related genes were comprehensively screened in a cohort of LVNC patients using targeted sequencing. Baseline and follow-up data were collected. The primary endpoint was a composite of death and heart transplantation. RESULTS:A total of 83 unrelated adult patients were included in analyses. Following stringent classification according to the American College of Medical Genetics and Genomics (ACMG) guidelines, 36 pathogenic variants of 14 genes were detected in 32 patients. Among them, 12 patients carried at least one nonsarcomere variant (NSV). At baseline, NSV carriers had a higher frequency of atrial fibrillation, but lower left ventricular ejection fraction, than did noncarriers. During a median follow-up of 4.2 years, NSV carriers experienced a higher rate of the primary endpoint compared with noncarriers. There was no significant difference in the rate between carriers of sarcomere variant (SV) and noncarriers, as well as between carriers of SV and NSV. The presence of NSV was associated with an increased risk of the primary endpoint independent of age, sex, and cardiac function (hazard ratio: 3.61, 95% confidence interval: 1.42-9.19, p = .002). CONCLUSION:NSV may act as a genetic modifier and worsen the clinical phenotype in patients with LVNC.

SUBMITTER: Li S

PROVIDER: S-EPMC6732340 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Clinical implications of sarcomere and nonsarcomere gene variants in patients with left ventricular noncompaction cardiomyopathy.

Li Shijie S Zhang Ce C Liu Nana N Bai Hui H Hou Cuihong C Pu Jielin J

Molecular genetics & genomic medicine 20190809 9

<h4>Background</h4>Robust data regarding genotype-phenotype correlations in left ventricular noncompaction cardiomyopathy (LVNC) are lacking.<h4>Methods</h4>About 72 cardiomyopathy-related genes were comprehensively screened in a cohort of LVNC patients using targeted sequencing. Baseline and follow-up data were collected. The primary endpoint was a composite of death and heart transplantation.<h4>Results</h4>A total of 83 unrelated adult patients were included in analyses. Following stringent c ...[more]

PMID: 31397097

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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 (LVNC) is a genetically and phenotypically heterogeneous cardiomyopathy in which myocardium consists of two, distinct compacted and noncompacted layers, and prominent ventricular trabeculations and deep intertrabecular recesses are present. LVNC is associated with an increased risk of heart failure, atrial and ventricular arrhythmias and thromboembolic events. Familial forms of primary sinus bradycardia have been attributed to alterations in HCN4. There are very few reports about the association between HCN4 and LVNC. The aim of our study was to characterize the clinical phenotype of families with LVNC and sinus bradycardia caused by pathogenic variants of the HCN4 gene.MethodsFrom March 2008 to July 2021, we enrolled six patients from four families with diagnosed isolated LVNC based on the clinical presentation, family history and echocardiographic and cardiovascular magnetic resonance (CMR) evidence of LVNC. Next generation sequencing (NGS) analysis was undertaken for the evaluation of the molecular basis of the disease in each family.ResultsA total of six children (median age 11 years) were recruited and followed prospectively for the median of 12 years. All six patients were diagnosed with LVNC by echocardiography, and five participants additionally by CMR. The presence of late gadolinium enhancement (LGE) was found in three children. Sinus bradycardia and dilation of the ascending aorta occurred in five studied patients. In four patients from three families, the molecular studies demonstrated the presence of rare heterozygous HCN4 variants.Conclusion(1) The HCN4 molecular variants influence the presence of a complex LVNC phenotype, sinus bradycardia and dilation of the ascending aorta. (2) The HCN4 alteration may be associated with the early presentation of clinical symptoms and the severe course of the disease. (3) It is particularly important to assess myocardial fibrosis not only within the ventricles, but also in the atria in patients with LVNC and sinus bradycardia.

Project description:Background: Left ventricular noncompaction cardiomyopathy (LVNC CMP) is a genetic cardiomyopathy. Genotype-phenotype correlation and clinical outcome of genetic variants in pediatric and adult LVNC CMP patients are still unclear. Methods: The retrospective multicenter study was conducted in unrelated index patients with LVNC CMP, diagnosed between the years 1987 and 2017, and all available family members. All index patients underwent next-generation sequencing for genetic variants in 174 target genes using the Illumina TruSight Cardio Sequencing Panel. Major adverse cardiac events (MACE) included mechanical circulatory support, heart transplantation, survivor of cardiac death, and/or all-cause death as combined endpoint. Results: Study population included 149 LVNC CMP patients with a median age of 27.8 (9.2-44.8) years at diagnosis; 58% of them were symptomatic, 18% suffered from non-sustained and sustained arrhythmias, and 17% had an implantable cardioverter defibrillator (ICD) implanted. 55/137 patients (40%) were ≤ 18 years at diagnosis. A total of 134 variants were identified in 87/113 (77%) index patients. 93 variants were classified as variant of unknown significance (VUS), 24 as likely pathogenic and 15 as pathogenic. The genetic yield of (likely) pathogenic variants was 35/113 (31%) index patients. Variants occurred most frequently in MYH7 (n=19), TTN (n = 10) and MYBPC3 (n = 8). Altogether, sarcomere gene variants constituted 42.5% (n = 57) of all variants. The presence or absence of (likely) pathogenic variants or variants in specific genes did not allow risk stratification for MACE. Reduced left ventricular (LV) systolic function and increased left ventricular end-diastolic diameter (LVEDD) were risk factors for event-free survival in the Kaplan-Meier analysis. Through multivariate analysis we identified reduced LV systolic function as the main risk factor for MACE. Patients with reduced LV systolic function were at a 4.6-fold higher risk for MACE. Conclusions: Genetic variants did not predict the risk of developing a MACE, neither in the pediatric nor in the adult cohort. Multivariate analysis emphasized reduced LV systolic function as the main independent factor that is elevating the risk for MACE. Genetic screening is useful for cascade screening to identify family members at risk for developing LVNC CMP.

Dataset Information

Clinical implications of sarcomere and nonsarcomere gene variants in patients with left ventricular noncompaction cardiomyopathy.

Publications

Clinical implications of sarcomere and nonsarcomere gene variants in patients with left ventricular noncompaction cardiomyopathy.

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