CHD2 haploinsufficiency is associated with developmental delay, intellectual disability, epilepsy and neurobehavioural problems

Abstract

BackgroundThe chromodomain helicase DNA binding domain (CHD) proteins modulate gene expression via their ability to remodel chromatin structure and influence histone acetylation. Recent studies have shown that CHD2 protein plays a critical role in embryonic development, tumor suppression and survival. Like other genes encoding members of the CHD family, pathogenic mutations in the CHD2 gene are expected to be implicated in human disease. In fact, there is emerging evidence suggesting that CHD2 might contribute to a broad spectrum of neurodevelopmental disorders. Despite growing evidence, a description of the full phenotypic spectrum of this condition is lacking.MethodsWe conducted a multicentre study to identify and characterise the clinical features associated with haploinsufficiency of CHD2. Patients with deletions of this gene were identified from among broadly ascertained clinical cohorts undergoing genomic microarray analysis for developmental delay, congenital anomalies and/or autism spectrum disorder.ResultsDetailed clinical assessments by clinical geneticists showed recurrent clinical symptoms, including developmental delay, intellectual disability, epilepsy, behavioural problems and autism-like features without characteristic facial gestalt or brain malformations observed on magnetic resonance imaging scans. Parental analysis showed that the deletions affecting CHD2 were de novo in all four patients, and analysis of high-resolution microarray data derived from 26,826 unaffected controls showed no deletions of this gene.ConclusionsThe results of this study, in addition to our review of the literature, support a causative role of CHD2 haploinsufficiency in developmental delay, intellectual disability, epilepsy and behavioural problems, with phenotypic variability between individuals.

Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy

“…15,16 Furthermore, epilepsy is a common feature of neurodevelopmental disorders, including autism spectrum disorder and intellectual disability, with many shared causative genes such as CHD2, GRIN2B, SCN2A, and SYNGAP1. 15,[17][18][19][20][21][22] Several recent studies have highlighted the usefulness of DES in clinical pediatric neurology practice, emphasizing a high diagnostic rate and impact on genetic counseling and patient management. 8,9,23 Data from small cohorts of patients with severe epilepsies also highlight the utility of DES for improving molecular diagnoses.…”

Chromodomain Helicase DNA-Binding Proteins in Stem Cells and Human Developmental Diseases

“…For CHD2, CHD6, and CHD7, mutations identified thus far are nonrecurrent (present in only individual cases), private mutations that account for a small fraction of ASD/ ID/epilepsy cases. In contrast to the rare isolated mutations in these three CHD genes, 13 different recurrent alleles of CHD8 have been observed in individuals with ASD/ID in association with macrocephaly and gastrointestinal disturbance [66,70,[75][76][77][78]. In cultured cells, CHD8 has been shown to bind CHD7 and to both bind and regulate p53 and inhibit its proapoptotic effects during development; thus, it is surprising that loss of CHD8 is not associated with broader phenotypic effects in humans [79][80][81][82].…”

“…CHD proteins in autism spectrum disorder, intellectual disability, and epilepsy Application of cytogenetic and next-generation sequencing technologies to large cohorts of individuals with autism spectrum disorder (ASD), intellectual disability (ID), and/or epilepsy has uncovered de novo and inherited heterozygous frameshift, nonsense, or copy dosage mutations in several CHD genes, including CHD2, CHD6, CHD7, and CHD8 [66][67][68][69][70][71][72][73][74]. For CHD2, CHD6, and CHD7, mutations identified thus far are nonrecurrent (present in only individual cases), private mutations that account for a small fraction of ASD/ ID/epilepsy cases.…”

A Novel Genetic Syndrome Caused by Haploinsufficiency of CHD2, a Regulator of Chromatin Structure

“…These two adult individuals had a similar phenotype to the patients previously published, including moderate ID, behavioural problems and generalized epilepsy (Table 1). Both patients also presented with differing degrees of scoliosis, which was noted in two of our microdeletion patients [2], in addition to adolescentonset truncal obesity. The authors speculate that haploinsufficiency of RGMA, encoding a member of the repulsive guidance molecule family that functions as an axon guidance protein in the developing and adult central nervous system, may contribute to the truncal obesity phenotype, while CHD2 haploinsufficiency is responsible for the neurodevelopmental phenotype and scoliosis [5].…”

“…Recently, we described chromosome 15q26.1 microdeletions encompassing CHD2 in a series of patients ascertained from six genetic diagnostic laboratories that perform chromosomal microarray analysis for patients broadly ascertained to have motor, speech and/or cognition delay (developmental delay), global developmental delay or ID, multiple congenital anomalies, and/or ASD [2]. Four from a total of 42,313 patients analyzed were identified with de novo CHD2 deletions, ranging in size from 78 kb to 237 kb ( Table 1).…”