Increased Burden of Ion Channel Gene Variants Is Related to Distinct Phenotypes in Pediatric Patients With Left Ventricular Noncompaction
Authors: Hirono Keiichi , Hata Yukiko , Miyao Nariaki , Okabe Mako , Takarada Shinya , Nakaoka Hideyuki , Ibuki Keijiro , Ozawa Sayaka , Origasa Hideki , Nishida Naoki , Ichida Fukiko , Takeda Atsuhito , Shimabukuro Atsuya , Akita Chisato , Fukumi Daichi , Nishihara Eiki , Tsuda Etsuko , Sakaguchi Heima , Ishida Hidekazu , Tomita Hideshi , Kise Hiroaki , Nagamine Hiroki , Uchiyama Hiroki , Katayama Hiromi , Ooki Hiroo , Nishikawa Hiroshi , Ono Hiroshi , Horigome Hisanori Sakazaki, Hitoshi , Muneuchi Jun , Yoshimoto Jun , Soumura Junpei , Kamada Masahiro , Yasuda Kazushi , Ikeda Kazuyuki , Yasuda Keiji , Kurosaki Kenichi , Mine Kenji , Ueno Kentaro , Takigiku Kiyohiro , Ogawa Kiyoshi , Inaguma Kotaro , Oyama Kotaro , Urayama Kotaro , Takahashi Kunihiko , Ohta Kunio , Nakazawa Makoto , Nakayashiro Mami , Ayusawa Mamoro , Toyono Manatomo , Nii Masaki , Miura Masaru , Fujino Mitsuhiro , Kuwabara Naoshi , Momoi Nobuo , Tsujii Nobuyuki , Motoki Noriko , Matsuo Osamu , Baba Reizo , Inuzuka Ryo , Kido Sachiko , Iwashima Satoru , Yasukochi Satoshi , Okada Seigo , Sato Seiichi , Mitsuru Seki , Kogaki Shigetoyo , Hoshino Shinsuke , Tsukano Shinya , Fujita Shuhei , Kimura Sumito , Urata Susumu , Kato Taichi , Toda Takako , Uchiyama Takamichi , Shindo Takahiro , Higaki Takashi , Kobayashi Tomio , Ozaki Tomoyasu , Tanaka Yasuhiko , Katsube Yasuhiro , Hamabuchi Yasunobu , Kajiyama Yo , Yoshida Yoko , Murakami Yosuke , Abe Yuriko , Hiraumi Yoshimi , Fukuda Yutaka , Odanaka Yutaka 
Published: June 2020

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.