Relevance to Autism

Three de novo loss-of-function (LoF) variants in the CHD2 gene were identified in ASD probands from the Simons Simplex Collection (Dong et al., 2014; Iossifov et al., 2014). De novo LoF and missense variants in CHD2 have also been identified in ASD probands from the Autism Sequencing Consortium, the Autism Clinical and Genetic Resources in China (ACGC) cohort, the Autism Genetic Resource Exchange, and the Autism Simplex Collection (De Rubeis et al., 2014; Wang et al., 2016; Stessman et al., 2017).Two additional de novo LoF variants in CHD2 were recently identified in ASD probands from a cohort of 262 Japanese trios in Takata et al., 2018; TADA-Denovo analysis demonstrated that this gene was significantly enriched for damaging de novo mutations in the Japanese ASD cohort, as well as in a combined dataset consisting of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium in addition to the Japanese ASD cohort. TADA analyses in Sanders et al., 2015, Feliciano et al., 2019, and Satterstrom et al., 2020 have all identified CHD2 as a candidate gene with a false discovery rate (FDR) 0.01; novel de novo protein-truncating variants in CHD2 were also identified in the last two reports. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified CHD2 as a gene reaching exome-wide significance (P < 2.5E-06). De novo loss-of-function and missense variants in the CHD2 gene had previously been identified in a total of 11 patients presenting with epilepsy and developmental delay/intellectual disability from four reports (Rauch et al., 2012; Carvill et al., 2013; Epi4K Consortium 2013; Suls et al., 2013); two cases with de novo LoF CHD2 variants from these reports also presented with ASD. De novo deletions affecting CHD2 had also been identified in 4 patients with recurrent clinical symptoms such as epilepsy, developmental delay/intellectual disability, and behavioral problem, including ASD in one case (Chenier et al., 2014).

Molecular Function

The CHD family of proteins is characterized by the presence of chromo (chromatin organization modifier) domains and SNF2-related helicase/ATPase domains. CHD genes alter gene expression possibly by modification of chromatin structure thus altering access of the transcriptional apparatus to its chromosomal DNA template.

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References

Model Summary

Both Chd2 nulls and hets show embryonic or perinatal lethality, defects in hematopoiesis, and cardiovascular abnormalities. Mutant cells demonstrate accumulative DNA damage markers and exhibit a decreased response to X-ray irradiation. Lordokyphosis and high incidence of lymphoma are also observed in Chd2 hets.

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