Submission Details

The CHD1 gene encodes an ATP-dependent chromatin remodeling protein. Although several de novo variants in CHD1 had been observed in large cohort studies of individuals with autism and developmental disorders (PMIDs: 25363760, 25363768, 28135719), the first report focusing on variants in CHD1 as a cause of autosomal dominant complex neurodevelopmental disorder was published in 2018 (Pilarowski et al., PMID: 28866611). Affected individuals present with developmental delay, hypotonia, and speech apraxia; other variable features include autism, seizures, and facial dysmorphic features.

Fifteen missense variants that have been reported in 15 probands in eight publications (PMIDs: 25363760, 25418537, 28135719, 28866611, 33057194, 35982159, 36625521; doi: 10.5734/JGM.2022.19.2.111) are included in this curation. Most of the variants are de novo and were reported in large exome sequencing studies of autism or developmental disorders, without detailed phenotype description or functional validation. A de novo missense variant reported by Sunwoo et al. (doi: 10.5734/JGM.2022.19.2.111) in a Korean male with clinical features compatible with Pilarowski-Bjornsson syndrome cannot formally be documented in the curation at this time, as this report does not have a PMID. Functional studies were performed for only two de novo missense variants that showed increased levels of a closed chromatin modification (H3K27me3) in patient fibroblasts (PMIDs: 28866611, 36625521). The mechanism of disease for missense variants has been hypothesized to be dominant negative (PMID: 28866611), but further functional studies are needed to clarify this issue. Two individuals with a CHD1 gene deletion have been reported with no obvious neurodevelopmental phenotype; one has isolated talipes equinovarus and the other cleft lip and palate (PMIDs: 28866611, 32918369). At least three patients with neurodevelopmental disorders and protein truncating variants have also been reported (PMIDs: 25418537, 33057194, 38174187), but were not scored in this curation because it is currently unclear if loss of function is a disease mechanism. CHD1 is constrained for both missense (Z = 4.21, gnomAD v2.1.1) and loss-of-function variants (pLI = 1). More evidence is needed to clarify the pathogenicity of missense variants reported without functional evidence and of protein truncating variants.

This gene-disease relationship is further supported by CHD1 biochemical function, as several other genes encoding chromodomain helicase DNA binding proteins, including CHD2, CHD3, CHD4, CHD5, CHD7, and CHD8, have also been implicated in neurodevelopmental disorders.

In summary, there is limited evidence to support the relationship between CHD1 and autosomal dominant complex neurodevelopmental disorder. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 17, 2024 (SOP Version 10).