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Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation

Published on: January 16, 2019

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

Keiichi Hirono¹, Yukiko Hata², Nariaki Miyao¹

¹Departments of Pediatrics (K.H., N.M., M.O., S.T., H.N., K.I., S.O., F.I.), Graduate School of Medicine, University of Toyama, Japan.

Circulation. Genomic and Precision Medicine

|July 1, 2020

Insights

Ion channel gene variants are linked to arrhythmias in pediatric left ventricular noncompaction (LVNC). This genetic insight aids in managing children with this hereditary heart condition.

Area of Science:

Cardiology
Genetics
Pediatrics

Background:

Left ventricular noncompaction (LVNC) is a hereditary cardiomyopathy with significant morbidity and mortality.
Genetic underpinnings, particularly ion channel gene variants, in pediatric LVNC remain incompletely understood.

Purpose of the Study:

To investigate the ion channel genetic landscape in pediatric LVNC.
To identify genotype-phenotype correlations in a large Japanese cohort of children with LVNC.

Main Methods:

A cohort of 206 children diagnosed with LVNC between 2002 and 2017 in Japan was studied.
Patients were classified based on LVNC presentation (e.g., congenital heart defects, arrhythmia, dilated phenotype, normal function).
Next-generation sequencing was employed to screen 182 cardiomyopathy-associated genes.

Main Results:

Pathogenic variants were identified in 40 genes in 87 patients, with 8.8% in ion channel genes.
Ion channel variants predominantly correlated with arrhythmia phenotypes, while sarcomere and mitochondrial variants were linked to dilated phenotypes.
Patients with ion channel variants showed a higher risk of arrhythmias like ventricular tachycardia and near-normal LV function parameters.

Conclusions:

This study is the first to explore genotype-phenotype correlations in pediatric LVNC focusing on ion channel variants.
Ion channel gene variants show a strong association with arrhythmia phenotypes in pediatric LVNC.
Genetic testing and precise phenotype characterization are crucial for targeted medical management in LVNC patients.

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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.

Keywords:

heart failure ion channels mortality pediatrics tachycardia

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