Human Gene Module / Chromosome 15 / CHD2

CHD2Chromodomain helicase DNA binding protein 2

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
31 / 83
Rare Variants / Common Variants
214 / 0
EAGLE Score
25
Strong Learn More
Aliases
CHD2, EEOC
Associated Syndromes
Tourette syndrome
Chromosome Band
15q26.1
Associated Disorders
DD/NDD, ADHD, ID, EP, EPS, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
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.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
Zebrafish
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CHD2 (83 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Kulkarni S et al. (2008) No -
2 Support Deletion of the RMGA and CHD2 genes in a child with epilepsy and mental deficiency Capelli LP , et al. (2011) No DD
3 Support Patterns and rates of exonic de novo mutations in autism spectrum disorders Neale BM , et al. (2012) Yes -
4 Support Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study Rauch A , et al. (2012) No Epilepsy, ASD
5 Primary Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1 Carvill GL , et al. (2013) No ID, ASD, DD
6 Positive Association De novo mutations in epileptic encephalopathies Epi4K Consortium , et al. (2013) No IS, LGS, DD, ID, ASD, ADHD
7 Recent Recommendation De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome Suls A , et al. (2013) No ASD, ADHD
8 Support - Lund C et al. (2014) No -
9 Support Convergence of genes and cellular pathways dysregulated in autism spectrum disorders Pinto D , et al. (2014) Yes -
10 Recent Recommendation CHD2 haploinsufficiency is associated with developmental delay, intellectual disability, epilepsy and neurobehavioural problems Chnier S , et al. (2014) No ASD, TS, ADHD
11 Support De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies EuroEPINOMICS-RES Consortium , et al. (2014) No -
12 Support De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder Dong S , et al. (2014) No -
13 Support De novo mutations in moderate or severe intellectual disability Hamdan FF , et al. (2014) No Microcephaly
14 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
15 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
16 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
17 Support - Thomas RH et al. (2015) No ASD, ADHD
18 Support - Trivisano M et al. (2015) No -
19 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
20 Support Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci Sanders SJ , et al. (2015) Yes -
21 Support - Pinto AM et al. (2016) Yes -
22 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
23 Support Genome-wide characteristics of de novo mutations in autism Yuen RK et al. (2016) Yes -
24 Support - Gauthier-Vasserot A et al. (2017) No -
25 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
26 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families Trujillano D , et al. (2016) No -
27 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases Stessman HA , et al. (2017) Yes -
28 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
29 Positive Association De Novo Coding Variants Are Strongly Associated with Tourette Disorder Willsey AJ , et al. (2017) No -
30 Support Genomic diagnosis for children with intellectual disability and/or developmental delay Bowling KM , et al. (2017) Yes ADHD, OCD
31 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
32 Support - Bernardo P et al. (2017) No Autistic features
33 Support Autism spectrum disorder recurrence, resulting of germline mosaicism for a CHD2 gene missense variant Lebrun N , et al. (2017) Yes ID, epilepsy/seizures
34 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
35 Support - Caputo D et al. (2018) No -
36 Support The first reported case of an inherited pathogenic CHD2 variant in a clinically affected mother and daughter Petersen AK , et al. (2018) No -
37 Support Autism-linked CHD gene expression patterns during development predict multi-organ disease phenotypes Kasah S , et al. (2018) No -
38 Recent Recommendation Chd2 Is Necessary for Neural Circuit Development and Long-Term Memory Kim YJ , et al. (2018) No -
39 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
40 Support The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders Jiao Q , et al. (2019) No DD
41 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population Monies D , et al. (2019) No -
42 Support - Routier L et al. (2019) Yes -
43 Support - Yamamoto T et al. (2019) No Autistic features, ID
44 Support Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability Borlot F , et al. (2019) No -
45 Support Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder Munnich A , et al. (2019) Yes -
46 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
47 Support CHD2-related epilepsy: novel mutations and new phenotypes Chen J , et al. (2019) No DD, ID, Afs
48 Support De Novo Damaging DNA Coding Mutations Are Associated With Obsessive-Compulsive Disorder and Overlap With Tourette's Disorder and Autism Cappi C , et al. (2019) No -
49 Support - Poisson A et al. (2020) No -
50 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
51 Support - Singh N et al. (2020) Yes -
52 Support Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use Husson T , et al. (2020) Yes -
53 Support - Mitta N et al. (2020) No -
54 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes ID
55 Support - Brunet T et al. (2021) No -
56 Support - Zou D et al. (2021) No -
57 Support - Trakadis Y et al. (2021) No DD, epilepsy/seizures
58 Support - Mahjani B et al. (2021) Yes -
59 Support - De Maria B et al. (2021) No ASD or autistic features, ADHD
60 Support - Li D et al. (2022) Yes -
61 Support - Wang Q et al. (2022) No -
62 Support - Brea-Fernández AJ et al. (2022) No -
63 Support - Luo X et al. (2022) No DD, ID
64 Support - Chuan Z et al. (2022) No -
65 Support - Wang X et al. (2022) No -
66 Support - Feng W et al. (2022) No Autistic features
67 Support - Stenshorne I et al. (2022) No -
68 Support - Zhou X et al. (2022) Yes -
69 Support - Lewis EMA et al. (2022) No -
70 Support - Shimelis H et al. (2023) No -
71 Support - Yuan B et al. (2023) Yes -
72 Support - Lasser M et al. (2023) Yes -
73 Support - Sheth F et al. (2023) Yes DD, ID
74 Support - Atefeh Mir et al. (2024) No -
75 Support - Ana Karen Sandoval-Talamantes et al. (2023) Yes ID
76 Support - Eleni Angelopoulou et al. (2023) No -
77 Support - Luigi Vetri et al. (2024) No -
78 Support - Marketa Wayhelova et al. (2024) No -
79 Support - Magdalena Badura-Stronka et al. (2024) No ID
80 Support - Francesca Cogliati et al. () No DD, epilepsy/seizures
81 Support - Lei Wan et al. (2024) Yes -
82 Support - Angela Clara-Hwang et al. (2024) No ASD, ADHD
83 Support - Axel Schmidt et al. (2024) No ID
Rare Variants   (214)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - stop_gained De novo - - 31993582 Singh N et al. (2020)
- - translocation De novo - - 18386809 Kulkarni S et al. (2008)
- - copy_number_loss De novo - - 24834135 Chnier S , et al. (2014)
- - copy_number_loss De novo - - 25672921 Thomas RH et al. (2015)
- - copy_number_loss De novo - - 34713950 De Maria B et al. (2021)
- - frameshift_variant De novo - - 28554332 Bowling KM , et al. (2017)
- p.Arg121Ter stop_gained De novo - - 25672921 Thomas RH et al. (2015)
- p.Gln909Ter stop_gained De novo - - 25672921 Thomas RH et al. (2015)
- - copy_number_loss De novo - Multiplex 24768552 Pinto D , et al. (2014)
- - copy_number_loss De novo - Simplex 22178256 Capelli LP , et al. (2011)
c.670C>T p.Arg224Ter stop_gained De novo - - 35386198 Luo X et al. (2022)
c.327C>G p.Val109%3D stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.934A>T p.Lys312Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.988C>T p.Gln330Ter stop_gained De novo - - 33004838 Wang T et al. (2020)
- p.Leu823Pro missense_variant De novo - - 25672921 Thomas RH et al. (2015)
- p.Trp548Arg missense_variant De novo - - 25672921 Thomas RH et al. (2015)
c.5035C>T p.Arg1679Ter stop_gained De novo - - 35386198 Luo X et al. (2022)
c.1345A>T p.Asn449Tyr stop_gained De novo - - 33004838 Wang T et al. (2020)
c.1239T>G p.Tyr413Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.2692C>T p.Gln898Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.443+4del - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.1810-2A>C - splice_site_variant De novo - - 24207121 Suls A , et al. (2013)
c.214G>T p.Gly72Cys missense_variant Unknown - - 34968013 Li D et al. (2022)
c.5035C>T p.Arg1679Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.1396C>T p.Arg466Ter stop_gained De novo - - 24207121 Suls A , et al. (2013)
c.4971G>A p.Trp1657Ter stop_gained De novo - - 24207121 Suls A , et al. (2013)
c.4489G>T p.Glu1497Ter stop_gained Unknown - - 32593896 Mitta N et al. (2020)
c.595C>T p.Arg199Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.667C>T p.Arg223Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.667C>T p.Arg223Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3937C>T p.Arg1313Ter stop_gained Unknown - - 34615535 Mahjani B et al. (2021)
- p.Leu1591Terfs frameshift_variant De novo - - 25672921 Thomas RH et al. (2015)
c.361C>T p.Arg121Ter stop_gained De novo - - 23708187 Carvill GL , et al. (2013)
- - copy_number_loss De novo - Simplex 39035822 Angela Clara-Hwang et al. (2024)
c.4012A>C p.Lys1338Gln missense_variant Unknown - - 35386198 Luo X et al. (2022)
c.1049A>C p.Gln350Pro missense_variant De novo - - 33004838 Wang T et al. (2020)
c.1234G>A p.Glu412Lys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2095C>T p.Arg699Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2699G>A p.Arg900Gln missense_variant De novo - - 33004838 Wang T et al. (2020)
c.2702C>G p.Ala901Gly missense_variant De novo - - 33004838 Wang T et al. (2020)
c.2740C>T p.Arg914Cys missense_variant De novo - - 33004838 Wang T et al. (2020)
c.1174A>G p.Thr392Ala missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2096G>A p.Arg699Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2426G>A p.Arg809Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2672C>A p.Pro891His missense_variant De novo - - 36881370 Yuan B et al. (2023)
c.4636G>T p.Arg1546Ter stop_gained Unknown - - 34363551 Trakadis Y et al. (2021)
c.3029C>G p.Ser1010Ter stop_gained Unknown - - 36475376 Shimelis H et al. (2023)
c.3346C>T p.Arg1116Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4034G>A p.Arg1345Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4483G>A p.Val1495Met missense_variant De novo - - 33004838 Wang T et al. (2020)
c.4507C>T p.Arg1503Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4516C>T p.Leu1506%3D missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4555G>A p.Ala1519Thr missense_variant De novo - - 33004838 Wang T et al. (2020)
c.5071C>T p.Pro1691Ser missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5129G>A p.Arg1710Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5362C>T p.Arg1788Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5369C>A p.Pro1790His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4602G>T p.Trp1534Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.522del p.Val175Ter frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.2506-2A>G - splice_site_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.1053-1G>C - splice_site_variant Unknown - Unknown 35266334 Wang Q et al. (2022)
c.1809+1G>T - splice_site_variant De novo - Simplex 35774528 Feng W et al. (2022)
c.3595+1G>T - splice_site_variant De novo - Simplex 35774528 Feng W et al. (2022)
c.1693A>G p.Ile565Val missense_variant Unknown - - 35571021 Chuan Z et al. (2022)
c.4278+1del - frameshift_variant De novo - Simplex 31677157 Chen J , et al. (2019)
c.*2273G>A - 3_prime_UTR_variant De novo - Simplex 27525107 Yuen RK et al. (2016)
c.3782G>A p.Trp1261Ter stop_gained De novo - - 31452935 Feliciano P et al. (2019)
c.1390A>T p.Arg464Ter stop_gained De novo - - 35979408 Stenshorne I et al. (2022)
c.1250G>A p.Trp417Ter stop_gained De novo - Simplex 35774528 Feng W et al. (2022)
c.1417C>T p.Gln473Ter stop_gained De novo - Simplex 35774528 Feng W et al. (2022)
c.5054G>A p.Arg1685His missense_variant De novo - - 27824329 Wang T , et al. (2016)
c.3947A>G p.Tyr1316Cys missense_variant De novo - - 30945278 Jiao Q , et al. (2019)
c.5120G>A p.Arg1707Gln missense_variant De novo - - 31677157 Chen J , et al. (2019)
c.5053C>T p.Arg1685Cys missense_variant Unknown - - 35571021 Chuan Z et al. (2022)
c.1809+1del - frameshift_variant De novo - Simplex 23020937 Rauch A , et al. (2012)
- p.Gly1575ValfsTer frameshift_variant De novo - - 25672921 Thomas RH et al. (2015)
c.4921C>T p.Gln1641Ter stop_gained De novo - - 28191889 Stessman HA , et al. (2017)
c.3571C>T p.Gln1191Ter stop_gained Unknown - - 39039281 Axel Schmidt et al. (2024)
c.3782G>A p.Trp1261Ter stop_gained De novo - Simplex 35774528 Feng W et al. (2022)
c.4636C>T p.Arg1546Ter stop_gained De novo - Simplex 35774528 Feng W et al. (2022)
c.3782G>A p.Trp1261Ter stop_gained De novo - Simplex 35982159 Zhou X et al. (2022)
c.4921C>T p.Gln1641Ter stop_gained De novo - Simplex 35982159 Zhou X et al. (2022)
c.2410C>T p.Arg804Ter stop_gained De novo - Simplex 31677157 Chen J , et al. (2019)
c.1861C>T p.Arg621Trp missense_variant De novo - - 31170314 Routier L et al. (2019)
- p.Gly491ValfsTer13 frameshift_variant De novo - - 25672921 Thomas RH et al. (2015)
c.693-1G>T - splice_site_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.4636C>T p.Arg1546Ter stop_gained De novo - Simplex 31677157 Chen J , et al. (2019)
c.5007G>A p.Trp1669Ter stop_gained De novo - Simplex 31677157 Chen J , et al. (2019)
- p.Arg1644LysfsTer22 frameshift_variant De novo - - 25672921 Thomas RH et al. (2015)
- p.Glu1412GlyfsTer64 frameshift_variant De novo - - 25672921 Thomas RH et al. (2015)
c.693-1G>T - splice_site_variant De novo - Simplex 31171384 Yamamoto T et al. (2019)
c.2716C>T p.Gln906Ter stop_gained Unknown - Simplex 28263302 C Yuen RK et al. (2017)
c.2173C>T p.Gln725Ter stop_gained De novo - Simplex 29346770 Takata A , et al. (2018)
c.335C>G p.Ser112Ter stop_gained De novo - Simplex 25356899 Hamdan FF , et al. (2014)
c.2352+1G>A - splice_site_variant De novo - Simplex 31406558 Munnich A , et al. (2019)
c.1642T>C p.Trp548Arg missense_variant De novo - - 23708187 Carvill GL , et al. (2013)
c.2468T>C p.Leu823Pro missense_variant De novo - - 23708187 Carvill GL , et al. (2013)
c.2663A>G p.Asp888Gly missense_variant De novo - - 38256219 Luigi Vetri et al. (2024)
- p.Gly491ValfsTer13 frameshift_variant De novo - - 23708187 Carvill GL , et al. (2013)
c.2727+46A>G - intron_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
- - copy_number_loss Unknown - Simplex 38328757 Magdalena Badura-Stronka et al. (2024)
c.272A>G p.Glu91Gly missense_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.4003G>T p.Glu1335Ter stop_gained De novo - Simplex 31914951 Poisson A et al. (2020)
c.1562C>A p.Ser521Ter stop_gained De novo - Simplex 34713950 De Maria B et al. (2021)
c.2963C>G p.Ser988Ter stop_gained De novo - Simplex 34713950 De Maria B et al. (2021)
c.2699G>A p.Arg900Gln missense_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.2699G>A p.Arg900Gln missense_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.1809G>T p.Lys603Asn missense_variant De novo - Simplex 35774528 Feng W et al. (2022)
c.1934C>T p.Thr645Met missense_variant De novo - Simplex 35774528 Feng W et al. (2022)
c.2095C>T p.Arg699Trp missense_variant De novo - Simplex 35774528 Feng W et al. (2022)
c.2291A>G p.His764Arg missense_variant De novo - Simplex 35774528 Feng W et al. (2022)
c.2593C>T p.Leu865Phe missense_variant De novo - Simplex 35774528 Feng W et al. (2022)
c.2005G>T p.Glu669Ter nonsynonymous_variant De novo - - 29529558 Caputo D et al. (2018)
c.4909C>T p.Arg1637Ter stop_gained De novo - Simplex 25363768 Iossifov I et al. (2014)
c.3931C>T p.Gln1311Ter stop_gained De novo - Simplex 31171384 Yamamoto T et al. (2019)
c.3937C>T p.Arg1313Ter stop_gained De novo - Simplex 34713950 De Maria B et al. (2021)
c.5035C>T p.Arg1679Ter stop_gained De novo - Simplex 34713950 De Maria B et al. (2021)
c.2999G>A p.Arg1000Gln missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.3521G>A p.Gly1174Asp missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.3782G>C p.Trp1261Ser missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.2068C>T p.His690Tyr missense_variant De novo - - 27848944 Trujillano D , et al. (2016)
c.2416dup p.Arg806LysfsTer20 frameshift_variant De novo - - 35386198 Luo X et al. (2022)
c.11_14del p.Asn4ArgfsTer89 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.3237G>T p.Lys1079Asn missense_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.3781T>C p.Trp1261Arg missense_variant De novo - Simplex 35774528 Feng W et al. (2022)
c.2537G>A p.Arg846Gln missense_variant De novo - Simplex 31677157 Chen J , et al. (2019)
c.2609G>A p.Gly870Asp missense_variant De novo - Simplex 31677157 Chen J , et al. (2019)
c.2644G>T p.Val882Phe missense_variant De novo - Simplex 31677157 Chen J , et al. (2019)
c.2740C>T p.Arg914Cys missense_variant De novo - Simplex 31677157 Chen J , et al. (2019)
c.4173dup p.Gln1392ThrfsTer17 frameshift_variant Unknown - - 34145886 Zou D et al. (2021)
c.4173dup p.Gln1392ThrfsTer17 frameshift_variant De novo - - 35386198 Luo X et al. (2022)
c.1265del p.Tyr422PhefsTer40 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.390C>T p.Ser130%3D splice_site_variant De novo - Simplex 35774528 Feng W et al. (2022)
c.1566C>G p.Phe522Leu missense_variant De novo - Simplex 31771860 Cappi C , et al. (2019)
c.727_728del p.Asp243Ter stop_gained De novo - Simplex 34713950 De Maria B et al. (2021)
c.4033C>T p.Arg1345Trp missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.4173dup p.Gln1392ThrfsTer17 frameshift_variant De novo - - 24614520 Lund C et al. (2014)
c.3455+2_3455+3insTG - splice_site_variant De novo - Simplex 35627293 Wang X et al. (2022)
c.3454C>G p.Arg1152Gly missense_variant De novo - Simplex 33619735 Brunet T et al. (2021)
c.2567A>G p.Asp856Gly missense_variant De novo - Simplex 22495311 Neale BM , et al. (2012)
c.2636C>T p.Ala879Val missense_variant De novo - Unknown 31130284 Monies D , et al. (2019)
c.1809_1809+1delinsTT - splice_site_variant De novo - Simplex 35627293 Wang X et al. (2022)
c.5153+2T>C - splice_site_variant Familial Paternal Simplex 31677157 Chen J , et al. (2019)
c.2095C>T p.Arg699Trp missense_variant De novo - Simplex 34713950 De Maria B et al. (2021)
c.2387T>C p.Leu796Ser missense_variant De novo - Simplex 34713950 De Maria B et al. (2021)
c.2698C>G p.Arg900Gly missense_variant De novo - Simplex 34713950 De Maria B et al. (2021)
c.4921C>T p.Gln1641Ter stop_gained De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.3783G>A p.Trp1261Ter stop_gained Familial Maternal Simplex 35627293 Wang X et al. (2022)
c.3455+2_345+3insTG p.? splice_site_variant De novo - Simplex 35774528 Feng W et al. (2022)
c.3787dup p.Val1263GlyfsTer4 frameshift_variant Unknown - - 31273778 Borlot F , et al. (2019)
c.3782G>C p.Trp1261Ser missense_variant De novo - Simplex 34713950 De Maria B et al. (2021)
c.4528G>A p.Gly1510Arg missense_variant De novo - Simplex 34713950 De Maria B et al. (2021)
c.1566C>G p.Phe522Leu missense_variant De novo - Simplex 28472652 Willsey AJ , et al. (2017)
c.1503G>A p.Lys501= splice_site_variant De novo - - 23934111 Epi4K Consortium , et al. (2013)
c.1730_1731dup p.Glu578MetfsTer11 frameshift_variant De novo - - 35386198 Luo X et al. (2022)
c.2843G>A p.Arg948Gln missense_variant Familial Both parents - 33004838 Wang T et al. (2020)
c.4216A>G p.Ser1406Gly missense_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.4987dup p.His1663ProfsTer4 frameshift_variant Unknown - - 34713950 De Maria B et al. (2021)
c.1570dup p.Ser524PhefsTer30 frameshift_variant De novo - - 37877434 Atefeh Mir et al. (2024)
c.947dup p.Tyr316Ter stop_gained De novo - Simplex 39035822 Angela Clara-Hwang et al. (2024)
c.3682del p.Glu1228SerfsTer21 frameshift_variant Unknown - - 36475376 Shimelis H et al. (2023)
c.3787dup p.Val1263GlyfsTer4 frameshift_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.4459G>A p.Asp1487Asn missense_variant De novo - Simplex 28191889 Stessman HA , et al. (2017)
c.4003G>T p.Glu1335Ter stop_gained De novo - Simplex 39035822 Angela Clara-Hwang et al. (2024)
c.1778dup p.Thr594AsnfsTer4 frameshift_variant Unknown - Simplex 31677157 Chen J , et al. (2019)
c.628G>T p.Glu210Ter stop_gained Familial Maternal Simplex 29740950 Petersen AK , et al. (2018)
c.4459G>A p.Asp1487Asn missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.3734dup p.Tyr1246IlefsTer13 frameshift_variant De novo - Simplex 35774528 Feng W et al. (2022)
c.4164dup p.Lys1389GlufsTer20 frameshift_variant De novo - Simplex 35774528 Feng W et al. (2022)
c.1820G>A p.Gly607Asp missense_variant Familial Paternal Simplex 37543562 Sheth F et al. (2023)
c.3734dup p.Tyr1246IlefsTer13 frameshift_variant De novo - Simplex 31677157 Chen J , et al. (2019)
c.4173dup p.Gln1392ThrfsTer17 frameshift_variant De novo - Simplex 31677157 Chen J , et al. (2019)
c.3998dup p.Gly1334TrpfsTer29 frameshift_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.937_938del p.Gly313LeufsTer11 frameshift_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.4036G>C p.Val1346Leu missense_variant Familial Paternal Multiplex 35774528 Feng W et al. (2022)
c.1903_1906del p.Asp635SerfsTer8 frameshift_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.2660_2661del p.Ser887Ter stop_gained De novo - Simplex 39035822 Angela Clara-Hwang et al. (2024)
c.1540G>C p.Gly514Arg missense_variant De novo - Simplex 39035822 Angela Clara-Hwang et al. (2024)
c.1934C>A p.Thr645Lys missense_variant De novo - Simplex 39035822 Angela Clara-Hwang et al. (2024)
c.2612G>A p.Gly871Asp missense_variant De novo - Simplex 39035822 Angela Clara-Hwang et al. (2024)
c.2707A>G p.Arg903Gly missense_variant De novo - Simplex 39035822 Angela Clara-Hwang et al. (2024)
c.4233_4236del p.Glu1412GlyfsTer64 frameshift_variant De novo - - 23708187 Carvill GL , et al. (2013)
c.4931_4932del p.Arg1644LysfsTer22 frameshift_variant De novo - - 23708187 Carvill GL , et al. (2013)
c.580C>T p.Gln194Ter stop_gained Familial Maternal Multiplex 38385826 Francesca Cogliati et al. ()
c.3787dup p.Val1263GlyfsTer4 frameshift_variant De novo - - 38321498 Marketa Wayhelova et al. (2024)
c.3112C>T p.Arg1038Cys missense_variant De novo - Simplex 39035822 Angela Clara-Hwang et al. (2024)
c.3497C>T p.Ser1166Leu missense_variant De novo - Simplex 39035822 Angela Clara-Hwang et al. (2024)
c.1961_1962del p.Lys654ArgfsTer15 frameshift_variant De novo - Simplex 35774528 Feng W et al. (2022)
c.2892_2895del p.Asn964LysfsTer4 frameshift_variant De novo - Simplex 25284784 Dong S , et al. (2014)
c.4949dup p.Gly1651TrpfsTer16 frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.4164del p.Met1388IlefsTer18 frameshift_variant De novo - Simplex 28910737 Bernardo P et al. (2017)
c.4173del p.Lys1391AsnfsTer15 frameshift_variant De novo - Simplex 34713950 De Maria B et al. (2021)
c.995_999del p.Val332GlyfsTer25 frameshift_variant Unknown - Simplex 32094338 Husson T , et al. (2020)
c.4256del p.Lys1419SerfsTer58 frameshift_variant De novo - Simplex 26262932 Trivisano M et al. (2015)
c.630_632del p.Glu210del inframe_deletion De novo - Simplex 39035822 Angela Clara-Hwang et al. (2024)
c.767del p.Gln256ArgfsTer12 frameshift_variant De novo - - 35322241 Brea-Fernández AJ et al. (2022)
c.4052_4053del p.Lys1351SerfsTer11 frameshift_variant De novo - Simplex 31677157 Chen J , et al. (2019)
c.1994C>T p.Pro665Leu missense_variant Unknown - - 38003033 Ana Karen Sandoval-Talamantes et al. (2023)
c.561del p.Lys188AsnfsTer61 frameshift_variant Unknown Not maternal - 34713950 De Maria B et al. (2021)
c.4771_4772del p.Leu1591AspfsTer32 frameshift_variant De novo - Simplex 34713950 De Maria B et al. (2021)
c.1008_1009delinsT p.Lys336AsnfsTer3 frameshift_variant De novo - Simplex 34713950 De Maria B et al. (2021)
c.1199del p.Ala400ValfsTer62 frameshift_variant De novo - Simplex 39035822 Angela Clara-Hwang et al. (2024)
c.5232G>A p.Met1744Ile missense_variant Familial Paternal Multi-generational 31677157 Chen J , et al. (2019)
c.4156dup p.Ser1386LysfsTer23 frameshift_variant De novo - Multi-generational 31677157 Chen J , et al. (2019)
c.4173dup p.Gln1392ThrfsTer17 frameshift_variant De novo - Simplex 39035822 Angela Clara-Hwang et al. (2024)
c.5041dup p.Met1681AsnfsTer21 frameshift_variant De novo - Simplex 39035822 Angela Clara-Hwang et al. (2024)
c.390C>T p.Ser130= splice_site_variant De novo - Simplex 25262651 EuroEPINOMICS-RES Consortium , et al. (2014)
c.1934C>T p.Thr645Met missense_variant De novo (germline mosaicism) - Multiplex 28960266 Lebrun N , et al. (2017)
c.4937_4940dup p.Tyr1648GlnfsTer20 frameshift_variant De novo - Simplex 39035822 Angela Clara-Hwang et al. (2024)
c.5094dup p.Pro1699AlafsTer3 frameshift_variant Unknown Not maternal - 27615324 Gauthier-Vasserot A et al. (2017)
c.1942C>T p.Pro648Ser missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.5035C>T p.Arg1679Ter stop_gained Familial Maternal Multi-generational 38125503 Eleni Angelopoulou et al. (2023)
c.4173dup p.Gln1392ThrfsTer17 frameshift_variant De novo - Multiplex (monozygotic twins) 26754451 Pinto AM et al. (2016)
c.4797_4812del p.His1599GlnfsTer210 frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

1/1/2021
1
icon
1

Score remained at 1

Description

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. 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).

Reports Added
[Disruption of chromodomain helicase DNA binding protein 2 (CHD2) causes scoliosis2008] [CHD2 mutations in Lennox-Gastaut syndrome2014] [CHD2 myoclonic encephalopathy is frequently associated with self-induced seizures2015] [CHD2 mutations are a rare cause of generalized epilepsy with myoclonic-atonic seizures2015] [Exome sequencing analysis in a pair of monozygotic twins re-evaluates the genetics behind their intellectual disability and reveals a CHD2 mutation2016] [Application of whole-exome sequencing to unravel the molecular basis of undiagnosed syndromic congenital neutropenia with intellectual disability2017] [CHD2 mutations: Only epilepsy? Description of cognitive and behavioral profile in a case with a new mutation2017] [CHD2-epilepsy: Polygraphic documentation of self-induced seizures due to fixation-off sensitivity2018] [Exome sequencing findings in 27 patients with myoclonic-atonic epilepsy: Is there a major genetic factor?2019] [Genomic backgrounds of Japanese patients with undiagnosed neurodevelopmental disorders2019] [Chromatin remodeling dysfunction extends the etiological spectrum of schizophrenia: a case report2020] [Juvenile myoclonic epilepsy mimic associated with CHD2 gene mutation2020] [Genotype-phenotype correlates of infantile-onset developmental & epileptic encephalopathy syndromes in South India: A single centre experience2020] [De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021]
10/1/2020
1
icon
1

Score remained at 1

Description

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. 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).

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
1/1/2020
1
icon
1

Score remained at 1

Description

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. 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).

Reports Added
[Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.2015] [De Novo Damaging DNA Coding Mutations Are Associated With Obsessive-Compulsive Disorder and Overlap With Tourette's Disorder and Autism.2019] [Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020] [Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use.2020]
10/1/2019
1S
icon
1

Score remained at 1

New Scoring Scheme
Description

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. 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).

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [CHD2-related epilepsy: novel mutations and new phenotypes.2019] [New Scoring Scheme]
7/1/2019
1S
icon
1S

Score remained at 1S

Description

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. 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).

Reports Added
[Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.2019] [Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability.2019] [Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder.2019]
4/1/2019
1S
icon
1S

Score remained at 1S

Description

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. 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).

Reports Added
[The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders.2019]
1/1/2019
1S
icon
1S

Score remained at 1S

Description

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. 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).

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
10/1/2018
1S
icon
1S

Score remained at 1S

Description

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. 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).

Reports Added
[Autism-linked CHD gene expression patterns during development predict multi-organ disease phenotypes.2018] [Chd2 Is Necessary for Neural Circuit Development and Long-Term Memory.2018]
7/1/2018
2S
icon
1S

Decreased from 2S to 1S

Description

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. 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).

10/1/2017
2S
icon
2S

Decreased from 2S to 2S

Description

De novo loss-of-function and missense variants in the CHD2 gene have been identified in a total of 11 patients presenting with epilepsy and developmental delay/intellectual disability from four reports (PMIDs 23020937, 23708187, 23934111, and 24207121). Two cases with de novo LoF CHD2 variants also presented with ASD (PMIDs 23708187 and 24207121). De novo deletions affecting CHD2 have 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 (PMID 24834135). Two additional de novo LoF variants in the CHD2 gene (one nonsense, one frameshift) were recently identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

Reports Added
[Autism spectrum disorder recurrence, resulting of germline mosaicism for a CHD2 gene missense variant.2017]
7/1/2017
2S
icon
2S

Decreased from 2S to 2S

Description

De novo loss-of-function and missense variants in the CHD2 gene have been identified in a total of 11 patients presenting with epilepsy and developmental delay/intellectual disability from four reports (PMIDs 23020937, 23708187, 23934111, and 24207121). Two cases with de novo LoF CHD2 variants also presented with ASD (PMIDs 23708187 and 24207121). De novo deletions affecting CHD2 have 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 (PMID 24834135). Two additional de novo LoF variants in the CHD2 gene (one nonsense, one frameshift) were recently identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

Reports Added
[Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.2017]
4/1/2017
2S
icon
2S

Decreased from 2S to 2S

Description

De novo loss-of-function and missense variants in the CHD2 gene have been identified in a total of 11 patients presenting with epilepsy and developmental delay/intellectual disability from four reports (PMIDs 23020937, 23708187, 23934111, and 24207121). Two cases with de novo LoF CHD2 variants also presented with ASD (PMIDs 23708187 and 24207121). De novo deletions affecting CHD2 have 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 (PMID 24834135). Two additional de novo LoF variants in the CHD2 gene (one nonsense, one frameshift) were recently identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

Reports Added
[Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [CHD2 haploinsufficiency is associated with developmental delay, intellectual disability, epilepsy and neurobehavioural problems.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Deletion of the RMGA and CHD2 genes in a child with epilepsy and mental deficiency.2011] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [De novo mutations in epileptic encephalopathies.2013] [De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome.2013] [Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012] [De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder.2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Genome-wide characteristics of de novo mutations in autism2016] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016] [Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017] [De novo mutations in moderate or severe intellectual disability.2014] [De Novo Coding Variants Are Strongly Associated with Tourette Disorder.2017] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]
1/1/2017
2S
icon
2S

Decreased from 2S to 2S

Description

De novo loss-of-function and missense variants in the CHD2 gene have been identified in a total of 11 patients presenting with epilepsy and developmental delay/intellectual disability from four reports (PMIDs 23020937, 23708187, 23934111, and 24207121). Two cases with de novo LoF CHD2 variants also presented with ASD (PMIDs 23708187 and 24207121). De novo deletions affecting CHD2 have 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 (PMID 24834135). Two additional de novo LoF variants in the CHD2 gene (one nonsense, one frameshift) were recently identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

Reports Added
[Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017]
10/1/2016
2S
icon
2S

Decreased from 2S to 2S

Description

De novo loss-of-function and missense variants in the CHD2 gene have been identified in a total of 11 patients presenting with epilepsy and developmental delay/intellectual disability from four reports (PMIDs 23020937, 23708187, 23934111, and 24207121). Two cases with de novo LoF CHD2 variants also presented with ASD (PMIDs 23708187 and 24207121). De novo deletions affecting CHD2 have 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 (PMID 24834135). Two additional de novo LoF variants in the CHD2 gene (one nonsense, one frameshift) were recently identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

Reports Added
[De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016]
7/1/2016
2S
icon
2S

Decreased from 2S to 2S

Description

De novo loss-of-function and missense variants in the CHD2 gene have been identified in a total of 11 patients presenting with epilepsy and developmental delay/intellectual disability from four reports (PMIDs 23020937, 23708187, 23934111, and 24207121). Two cases with de novo LoF CHD2 variants also presented with ASD (PMIDs 23708187 and 24207121). De novo deletions affecting CHD2 have 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 (PMID 24834135). Two additional de novo LoF variants in the CHD2 gene (one nonsense, one frameshift) were recently identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

Reports Added
[Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Genome-wide characteristics of de novo mutations in autism2016]
1/1/2016
2S
icon
2S

Decreased from 2S to 2S

Description

De novo loss-of-function and missense variants in the CHD2 gene have been identified in a total of 11 patients presenting with epilepsy and developmental delay/intellectual disability from four reports (PMIDs 23020937, 23708187, 23934111, and 24207121). Two cases with de novo LoF CHD2 variants also presented with ASD (PMIDs 23708187 and 24207121). De novo deletions affecting CHD2 have 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 (PMID 24834135). Two additional de novo LoF variants in the CHD2 gene (one nonsense, one frameshift) were recently identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

Reports Added
[Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [CHD2 haploinsufficiency is associated with developmental delay, intellectual disability, epilepsy and neurobehavioural problems.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Deletion of the RMGA and CHD2 genes in a child with epilepsy and mental deficiency.2011] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [De novo mutations in epileptic encephalopathies.2013] [De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome.2013] [Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012] [De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder.2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014]
1/1/2015
2S
icon
2S

Decreased from 2S to 2S

Description

De novo loss-of-function and missense variants in the CHD2 gene have been identified in a total of 11 patients presenting with epilepsy and developmental delay/intellectual disability from four reports (PMIDs 23020937, 23708187, 23934111, and 24207121). Two cases with de novo LoF CHD2 variants also presented with ASD (PMIDs 23708187 and 24207121). De novo deletions affecting CHD2 have 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 (PMID 24834135). Two additional de novo LoF variants in the CHD2 gene (one nonsense, one frameshift) were recently identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

Reports Added
[Large-scale discovery of novel genetic causes of developmental disorders.2014]
10/1/2014
3S
icon
2S

Decreased from 3S to 2S

Description

De novo loss-of-function and missense variants in the CHD2 gene have been identified in a total of 11 patients presenting with epilepsy and developmental delay/intellectual disability from four reports (PMIDs 23020937, 23708187, 23934111, and 24207121). Two cases with de novo LoF CHD2 variants also presented with ASD (PMIDs 23708187 and 24207121). De novo deletions affecting CHD2 have 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 (PMID 24834135). Two additional de novo LoF variants in the CHD2 gene (one nonsense, one frameshift) were recently identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

Reports Added
[De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014]
7/1/2014
No data
icon
3S

Increased from No data to 3S

Description

De novo loss-of-function and missense variants in the CHD2 gene have been identified in a total of 11 patients presenting with epilepsy and developmental delay/intellectual disability from four reports (PMIDs 23020937, 23708187, 23934111, and 24207121). Two cases with de novo LoF CHD2 variants also presented with ASD (PMIDs 23708187 and 24207121). De novo deletions affecting CHD2 have 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 (PMID 24834135)

4/1/2014
No data
icon
3S

Increased from No data to 3S

Description

De novo loss-of-function and missense variants in the CHD2 gene have been identified in a total of 11 patients presenting with epilepsy and developmental delay/intellectual disability from four reports (PMIDs 23020937, 23708187, 23934111, and 24207121). Two cases with de novo LoF CHD2 variants also presented with ASD (PMIDs 23708187 and 24207121). De novo deletions affecting CHD2 have 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 (PMID 24834135)

Reports Added
[CHD2 haploinsufficiency is associated with developmental delay, intellectual disability, epilepsy and neurobehavioural problems.2014] [Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.2014]
Krishnan Probability Score

Score 0.47577089053778

Ranking 8536/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99999999884542

Ranking 100/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Iossifov Probability Score

Score 0.997

Ranking 12/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 6.7367674090958E-6

Ranking 7/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Larsen Cumulative Evidence Score

Score 63

Ranking 24/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.57451349814661

Ranking 156/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
ADARB2 adenosine deaminase, RNA-specific, B2 Human Protein Binding 105 Q9NS39
ARID5B AT rich interactive domain 5B (MRF1-like) Human Protein Binding 84159 Q14865
BCKDK branched chain ketoacid dehydrogenase kinase Human Protein Binding 10295 A8MY43
BEND7 BEN domain containing 7 Human Protein Binding 222389 Q8N7W2
CENPV centromere protein V Human Protein Binding 201161 Q7Z7K6
FAM120C family with sequence similarity 120C Human Protein Binding 54954 Q9NX05
INO80B INO80 complex subunit B Human Protein Binding 83444 Q9C086
Myl3 myosin, light chain 3, alkali; ventricular, skeletal, slow Mouse Direct Regulation 17897 P09542
Myod1 myogenic differentiation 1 Mouse Protein Binding 17927 P10085
Myog myogenin (myogenic factor 4) Mouse Direct Regulation 17928 P12979
PARP1 poly (ADP-ribose) polymerase 1 Human Protein Binding 142 P09874
RBAK RB-associated KRAB zinc finger Human Protein Binding 57786 Q9NYW8
RREB1 ras responsive element binding protein 1 Human Protein Binding 6239 Q92766
SPATA12 spermatogenesis associated 12 Human Protein Binding 353324 Q7Z6I5
THAP1 THAP domain containing, apoptosis associated protein 1 Human Protein Binding NM_018105 Q9NVV9
WDR33 WD repeat domain 33 Human Protein Binding 55339 Q9C0J8
ZC3HAV1 zinc finger CCCH-type, antiviral 1 Human Protein Binding 56829 Q7Z2W4
ZMYND11 zinc finger, MYND-type containing 11 Human Protein Binding 10771 Q5BJG6
ZNF174 zinc finger protein 174 Human Protein Binding 7727 Q15697
ZNF317 zinc finger protein 317 Human Protein Binding 57693 Q96PQ6
ZNF462 zinc finger protein 462 Human Protein Binding 58499 Q96JM2
ZNF592 zinc finger protein 592 Human Protein Binding 9640 Q92610
ZNF687 zinc finger protein 687 Human Protein Binding 57592 Q8N1G0
ZNF768 zinc finger protein 768 Human Protein Binding 79724 Q9H5H4
ZSCAN12 zinc finger and SCAN domain containing 12 Human Protein Binding 9753 O43309
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