CHD4 variants are associated with childhood idiopathic epilepsy with sinus arrhythmia

• Published in: CNS neuroscience & therapeutics Vol. 27; no. 10; pp. 1146 - 1156
• Main Authors: Liu, Xiao‐Rong, Ye, Ting‐Ting, Zhang, Wen‐Jun, Guo, Xuan, Wang, Jie, Huang, Shao‐Ping, Xie, Long‐Shan, Song, Xing‐Wang, Deng, Wei‐Wen, Li, Bing‐Mei, He, Na, Wu, Qian‐Yi, Zhuang, Min‐Zhi, Xu, Meng, Shi, Yi‐Wu, Su, Tao, Yi, Yong‐Hong, Liao, Wei‐Ping
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.10.2021; John Wiley and Sons Inc
• Subjects: Adolescent; Arrhythmia; Arrhythmia, Sinus - genetics; Cardiac arrhythmia; Cell cycle; CHD4 gene; Child; childhood idiopathic epilepsy; Children; Cohort Studies; Convulsions & seizures; Developmental disabilities; DNA helicase; Electroencephalography; Epilepsy; Epilepsy - genetics; Families & family life; Female; Fetuses; Genes; Genetic Variation; Genomes; Genotype; Humans; Magnetic resonance imaging; Male; Mi-2 Nucleosome Remodeling and Deacetylase Complex - genetics; Middle Aged; Missense mutation; Mutation; Mutation, Missense; Original; Patients; Phenotype; Phenotypic variations; Population; Proteins; sinus arrhythmia; Sinuses; Software; Statistical analysis; Whole Exome Sequencing; CHD4 gene; sinus arrhythmia; childhood idiopathic epilepsy
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.13692

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. CHD4 missense mutations associated with multisystem developmental abnormalities were clustered in the central region from SNF2‐like region to DUF 1087 domain, while the variants associated with other mild phenotypes were located outside this region. The potentially molecular sub‐regional effects of missense mutations may explain for the phenotypic severity of CHD4 mutations and would help understand the underlying mechanisms of phenotypic variation.