Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy

Abstract

Located in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%). Epilepsy types were variable, with West syndrome observed in three patients, generalized tonic–clonic seizures in two, and other subtypes observed in one individual each. Our findings suggest that, in line with other CHD-related disorders, heterozygous CHD5 variants are associated with a variable neurodevelopmental syndrome that includes intellectual disability with speech delay, epilepsy, and behavioral problems as main features.

Analysis of recent shared ancestry in a familial cohort identifies coding and noncoding autism spectrum disorder variants

“…CHD5 is a chromatin remodeler that regulates neuronal differentiation and cortical development 66 , and its disruption in mice results in ASD-like behaviors 67 . A recent report identified heterozygous missense and LoF mutations in CHD5 in an autosomal dominant neurodevelopmental disorder of intellectual disability, developmental delay, language deficits, and epilepsy 68 . GRB10 is involved in neuronal development and social dominance behavior in mice, and has a tissue-specific and imprinted expression pattern where the paternal allele is exclusively expressed in neurons 69 .…”

Role of ATP-dependent chromatin remodelers in hematopoietic stem and progenitor cell maintenance

“…In general, most CHD proteins are important for chromatin access and gene expression in cell-type specific manner. Although the role of CHDs in neural stem cells and neurodevelopmental process has been well documented [8,13,[15][16][17][18], their regulatory functions in HSPC maintenance and differentiation have only been appreciated recently.…”

Mammalian Resilience Revealed by a Comparison of Human Diseases and Mouse Models Associated With DNA Helicase Deficiencies

“…CHD5 is expressed in the nervous system and testes ( Thompson et al, 2003 ; Zhuang et al, 2014 ). Although CHD5 is a tumor suppressor gene frequently altered in many human cancers ( Bagchi et al, 2007 ), patients with CHD5 mutations do not develop tumors ( Parenti et al, 2021 ), suggesting that germline CHD5 alterations do not increase cancer risk. CHD5-deficient patients demonstrate dominant neurodevelopment disorders, including behavioral disturbances, epilepsy, and intellectual disability ( Parenti et al, 2021 ).…”