CHD1

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

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).

Inheritance Pattern: AD

Disease ID:MONDO:0060568

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0060568

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0060568

Submitter: G2P

Inheritance Pattern: Unknown

Disease ID:MONDO:0060568

Submitter: Labcorp Genetics (formerly Invitae)