CHD4 was first reported in relation to autosomal dominant syndromic intellectual disability in 2016 (Sifrim et al., PMID: 27479907; Weiss et al., PMID: 27616479); the terms CHD4 neurodevelopmental disorder and Sifrim-Hitz-Weiss syndrome have also been used in the literature to describe patients with CHD4 variants. CHD4 encodes a chromodomain-helicase DNA-binding protein that is involved in chromatin remodeling, epigenetic regulation of gene transcription, DNA repair, and cell cycle progression. Affected individuals present with motor and speech delays, mild-to-moderate intellectual disability, brain anomalies, heart defects, and dysmorphic facial features; other variable features include hypotonia, hearing loss, hypogonadotrophic hypogonadism in males, limb or skeletal anomalies, and Moyamoya angiopathy (PMIDs: 31388190, 31474762).
Twenty-three unique variants (22 missense, 1 inframe indel) reported in 24 probands in 3 publications (PMIDs: 27616479, 31388190, 31474762) are included in this curation; 1 recurrent missense variant (p.Arg1127Gln) was reported in 2 unrelated probands. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Most variants are de novo. The mechanism of disease is suggested to be dominant negative or gain-of-function (PMID: 31388190). Four patients with protein truncating variants have also been reported (PMIDs: 31388190, 31474762), but were not scored in this curation due to lack of consistent clinical features and unclear disease mechanism. Additional genetic evidence is needed to determine whether loss of function is a mechanism of pathogenicity. CHD4 is highly constrained for both missense (Z = 6.34, gnomAD v2.1.1) and loss-of-function variants (pLI = 1).
This gene-disease relationship is also supported by experimental evidence, including in vitro functional assays, biochemical function, protein interaction, and cell culture models (PMIDs: 31388190, 29795351, 30409903, 32647123). Patient variants result in decreased ATPase and nucleosome remodeling activity (PMID: 31388190).
In summary, there is definitive evidence supporting the relationship between CHD4 and autosomal dominant syndromic intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 19, 2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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