Open AccessCHD4 variants are associated with childhood idiopathic epilepsy with sinus arrhythmia
Author(s) -
Liu XiaoRong,
Ye TingTing,
Zhang WenJun,
Guo Xuan,
Wang Jie,
Huang ShaoPing,
Xie LongShan,
Song XingWang,
Deng WeiWen,
Li BingMei,
He Na,
Wu QianYi,
Zhuang MinZhi,
Xu Meng,
Shi YiWu,
Su Tao,
Yi YongHong,
Liao WeiPing
Publication year - 2021
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.13692
Subject(s) - missense mutation , epilepsy , chromodomain , genetics , exome , exome sequencing , mutation , medicine , gene , biology , bioinformatics , neuroscience , helicase , rna
Aims CHD4 gene, encoding chromodomain helicase DNA‐binding protein 4, is a vital gene for fetal development. In this study, we aimed to explore the association between CHD4 variants and idiopathic epilepsy. Methods Trios‐based whole‐exome sequencing was performed in a cohort of 482 patients with childhood idiopathic epilepsy. The Clinical Validity Framework of ClinGen and an evaluating method from five clinical‐genetic aspects were used to determine the association between CHD4 variants and epilepsy. Results Four novel heterozygous missense mutations in CHD4 , including two de novo mutations (c.1597A>G/p.K533E and c.4936G>A/p.E1646K) and two inherited mutations with co‐segregation (c.856C>G/p.P286A and c.4977C>G/p.D1659E), were identified in four unrelated families with eight individuals affected. Seven affected individuals had sinus arrhythmia. From the molecular sub‐regional point of view, the missense mutations located in the central regions from SNF2‐like region to DUF1087 domain were associated with multisystem developmental disorders, while idiopathic epilepsy‐related mutations were outside this region. Strong evidence from ClinGen Clinical Validity Framework and evidences from four of the five clinical‐genetic aspects suggested an association between CHD4 variants and epilepsy. Conclusions CHD4 was potentially a candidate pathogenic gene of childhood idiopathic epilepsy with arrhythmia. The molecular sub‐regional effect of CHD4 mutations helped explaining the mechanisms underlying phenotypic variations.