Increased Burden of Ion Channel Gene Variants Is Related to Distinct Phenotypes in Pediatric Patients With Left Ventricular Noncompaction

Abstract

Background: Left ventricular noncompaction (LVNC) is a hereditary type of cardiomyopathy. Although it is associated with high morbidity and mortality, the related ion channel gene variants in children have not been fully investigated. This study aimed to elucidate the ion channel genetic landscape of LVNC and identify genotype-phenotype correlations in a large Japanese cohort. Methods: We enrolled 206 children with LVNC from 2002 to 2017 in Japan. LVNC was classified as follows: LVNC with congenital heart defects, arrhythmia, dilated phenotype, or normal function. In the enrolled patients, 182 genes associated with cardiomyopathy were screened using next-generation sequencing. Results: We identified 99 pathogenic variants in 40 genes in 87 patients. Of the pathogenic variants, 8.8% were in genes associated with channelopathies, 27% were in sarcomere genes, and 11.5% were in mitochondrial genes. Ion channel gene variants were mostly associated with the arrhythmia classification, whereas sarcomere and mitochondrial gene variants were associated with the dilated phenotype. Echocardiography revealed that the group with ion channel gene variants had almost normal LV ejection fraction and LV diastolic diameter Z scores. Fragmented QRS, old age, and an arrhythmia phenotype were the most significant risk factors for ventricular tachycardia ( P =0.165, 0.0428, and 0.0074, respectively). Moreover, the group with ion channel variants exhibited a greater risk of a higher prevalence of arrhythmias such as ventricular tachycardia, rather than congestive heart failure. Conclusions: This is the first study that focused on genotype-phenotype correlations in a large pediatric LVNC patient cohort with ion channel gene variants that were determined using next-generation sequencing. Ion channel gene variants were strongly correlated with arrhythmia phenotypes. Genetic testing and phenotype specification allow for appropriate medical management of specific LVNC targets.

Clinical Presentation of Left Ventricular Noncompaction Cardiomyopathy and Bradycardia in Three Families Carrying <em>HCN4</em> Pathogenic Variants

“…HCN4 variants accounted for 10% of (likely) pathogenic variants identified in a cohort of 95 adults diagnosed with LVNC by Richard et al [29] as well as in a similar group reported on by Cambon-Viala et al [30]. In a recent study, Hirono et al [31] found two children with HCN4-related LVNC among 206 patients aged less than 16 years.…”

Case Report: Biventricular Noncompaction Cardiomyopathy With Pulmonary Stenosis and Bradycardia in a Fetus With KCNH2 Mutation

“…In addition, in the study by Wang et al (2017 ), the number of rare variants in KCNH2 was significantly enriched in LVNC patients compared with the control group, further supporting the association between LVNC and KCNH2 mutation. In several recent independent LVNC cohorts, the variation burden of ion channel genes were as high as 8.8–14.7 ( Hirono et al, 2020 ; Cambon-Viala et al, 2021 ; Miszalski-Jamka et al, 2017 ; Wang et al, 2017 ), significantly higher than in the general population. This suggests that ion-channel dysfunction may play a role in the pathogenesis of LVNC( Milano et al, 2014 ; Nakashima et al, 2013 ; Shan et al, 2008 ; Towbin, 2014 ).…”

Thromboembolic events in left ventricular non-compaction: comparison between children and adults – a systematic review and meta-analysis

“…We analysed the factors associated with TE in the paediatric patients 1 5 7 22 Table 1. shows the univariate and multivariate risk estimates for TE.…”

“…In adults who underwent echocardiography, the prevalence of LVNC was reported to be 0.05%–0.14% 3 4. The clinical manifestations of LVNC vary widely from neonates to adults, which range from asymptomatic cases to end-stage heart failure (HF), potentially necessitating mechanical circulatory support and/or cardiac transplantation 5–7. The annual all-cause mortality rate from LVNC is 2.16% 8.…”