Karimi et al., 2025 performed DNA methylation analysis studies on a cohort of individuals with Sifrim-Hitz-Weiss syndrome and found a recognizable episignature in individuals with pathogenic CHD4 missense variants within the ATP helicase domain; conversely, individuals with truncating CHD4 variants exhibited a different episignature and phenotype with a higher rate of autism spectrum disorder (6/7 individuals with truncating variants vs. 1/20 with missense variants). De novo and inherited loss-of-function variants and damaging de novo missense variants in CHD4 have also been reported in ASD probands from the Simons Simplex Collection, the SPARK cohort, the Autism Sequencing Consortium, the Autism Simplex Collection, and the iHART cohort (Iossifov et al., 2014; Stessman et al., 2017; Ruzzo et al., 2019; Zhou et al., 2022; Fu et al., 2022). Larrigan et al., 2023 demonstrated that telecephalon-specific conditional knockout of Chd4 in mice resulted in increased repetitive behaviors, a phenotype that was more apparent in female animals.
Molecular Function
The product of this gene belongs to the SNF2/RAD54 helicase family. It represents the main component of the nucleosome remodeling and deacetylase complex and plays an important role in epigenetic transcriptional repression. Heterozygous mutations in the CHD4 gene are responsible for Sifrim-Hitz-Weiss syndrome (OMIM 617159), an autosomal dominant intellectual developmental disorder with variable congenital defects affecting other systems, including cardiac, skeletal, and urogenital.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Discovery of a DNA methylation profile in individuals with Sifrim-Hitz-Weiss syndrome
