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.

中文翻译：

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离子通道基因变异的负担增加与左心室致密化不全的儿科患者的不同表型有关。

背景：左心室致密化不全（LVNC）是一种遗传性心肌病。尽管它与高发病率和死亡率有关，但尚未充分研究儿童中相关的离子通道基因变异。本研究旨在阐明 LVNC 的离子通道遗传景观，并在日本大型队列中确定基因型-表型相关性。方法：我们在日本招募了 206 名 2002 年至 2017 年的 LVNC 儿童。LVNC 分类如下：先天性心脏缺陷、心律失常、扩张表型或功能正常的 LVNC。在纳入的患者中，使用二代测序技术筛选了 182 个与心肌病相关的基因。结果：我们在 87 名患者的 40 个基因中发现了 99 个致病变异。在致病变异中，8.8% 位于与通道病相关的基因中，27% 在肌节基因中，11.5% 在线粒体基因中。离子通道基因变异主要与心律失常分类相关，而肌节和线粒体基因变异与扩张表型相关。超声心动图显示，离子通道基因变异组的 LV 射血分数和 LV 舒张直径几乎正常Z分数。QRS 碎裂、高龄和心律失常表型是室性心动过速的最重要危险因素（分别为P =0.165、0.0428 和 0.0074）。此外，离子通道变异组表现出更高的心律失常患病率（如室性心动过速，而不是充血性心力衰竭）的风险。使用下一代测序确定的离子通道基因变异。离子通道基因变异与心律失常表型密切相关。基因检测和表型规范允许对特定 LVNC 目标进行适当的医学管理。