Abstract
Pathogenic variants in CHD2 have been reported to have a wide range of phenotypic variability in neurodevelopmental disorders, such as early-onset epileptic encephalopathy, developmental delay, and behavior problems. So far, there is no clear correlation between genotypes and phenotypes. This study reports a Chinese patient with a novel heterozygous CHD2 mutation (c.4318C>T, pArg1440*). Her main clinical manifestations include developmental delay, myoclonic epilepsy, and hypothyroidism. Then, we reviewed a total of 144 individuals carrying CHD2 variants with epileptic encephalopathy. In terms of clinical manifestations, these patients are usually described with variable epilepsy phenotypes, including idiopathic photosensitive occipital epilepsy, Dravet syndrome, Jeavons syndrome, Lennox–Gastaut syndrome, juvenile myoclonic epilepsy, and non-specific epileptic encephalopathy. Among them, myoclonic seizures and generalized tonic-clonic seizures are the main seizure types in all patients hosting CHD2 single-nucleotide or indel variants (non-CNVs). At the molecular level, there are 102 types of CHD2 non-CNVs in 126 patients, almost one mutational type corresponding to one person, and there is no difference in the incidence ratio of each position. Furthermore, we summarized that a small proportion of patients inherited CHD2 variants, and not all patients with CHD2 variants had seizures. Importantly, the phenotypes, especially seizures control and fever sensitivity, and genotypes had a relative association. These results enriched the database of CHD2-relative neurodevelopmental disorders and provided a theoretical foundation for researching the relationship between genotypes and phenotypes.
Highlights
Chromodomain helicase DNA-binding protein 2 (CHD2, MIM: 615369) is a member of the CHD family, which is only known to cause the brain-restricted phenotypes when disrupted in humans
The papers and review articles on these cases were saved; 3) using the “CHD2” gene as the keyword, relevant papers in the HGMD database were acquired, downloaded, screened, and reserved, and these papers were associated with CHD2-related epileptic encephalopathy; 4) the collected review articles were used to confirm the conclusions from the obtained papers and complement the lacking literature; 5) patient information, including clinical information, neuroimaging, physical, and genetic findings, was extracted from these papers, such as gender, inheritance, and diagnostic findings; and 6) all results were checked by more than two researchers, and the opposite consequences were verified after discussion
A girl with developmental delay and myoclonic epilepsy caused by a new mutation c.4318C>T in the CHD2 gene was studied using whole-exome sequencing (WES)
Summary
Chromodomain helicase DNA-binding protein 2 (CHD2, MIM: 615369) is a member of the CHD family, which is only known to cause the brain-restricted phenotypes when disrupted in humans. Some studies have demonstrated that pathogenic variants of the CHD2 gene are associated with childhood-onset developmental and epileptic encephalopathy (DEE), which is a severe form of neurodevelopmental disorder with a wide range of phenotypic variability, including autism spectrum. CHD2 Variants Related Epileptic Encephalopathy disorder (ASD), intellectual disability (ID), developmental delay, microcephalus, behavioral anomalies, facial dysmorphisms, and several types of epilepsy (Carvill and Mefford, 2015; Thomas et al , 2015; Verhoeven et al, 2016; Chen et al, 2020). Chen et al presented the largest single case series of patients with CHD2-related epilepsy and comprehensively reviewed 53 published cases in the literature through seizure onset age, seizure types, developmental outcome, electroencephalogram (EEG), brain magnetic resonance imaging (MRI), and diagnoses, among others, which improved the understanding on the relationship between genotype and phenotype (Chen et al, 2020). We systematically reviewed the published literature, provided a thorough overview of clinical, neuroimaging, physical, and genetic findings in CHD2-related epilepsy patients, and built the possible relationship between genotypes and phenotypes
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