Human Gene Module / Chromosome 15 / CHD2

CHD2Chromodomain helicase DNA binding protein 2

Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
10 / 22
Rare Variants / Common Variants
39 / 0
Aliases
CHD2, 
Associated Syndromes
Tourette syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
15q26.1
Associated Disorders
EP, ASD, EPS, DD/NDD, ADHD, ID
Relevance to Autism

Six de novo variants in the CHD2 gene (four truncating variants and two missense variants disrupting highly conserved residues in the SNF2-related helicase/ATPase domain) were identified in individuals with a wide range of epileptic encephalopathies; all six of these individuals exhibited moderate-to-severe intellectual disability, and two individuals also displayed ASD (Carvill et al., 2013). De novo variants affecting this gene have also been found in individuals with ASD (Neale et al., 2012) and intellectual disability (Rauch et al., 2012).

Molecular Function

This gene enocdes a member of the CHD family of proteins, which are 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.

Reports related to CHD2 (22 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Deletion of the RMGA and CHD2 genes in a child with epilepsy and mental deficiency. Capelli LP , et al. (2011) No DD
2 Support Patterns and rates of exonic de novo mutations in autism spectrum disorders. Neale BM , et al. (2012) Yes -
3 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
4 Primary Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Carvill GL , et al. (2013) No ID, ASD, DD
5 Positive association De novo mutations in epileptic encephalopathies. Epi4K Consortium , et al. (2013) No IS, LGS, DD, ID, ASD, ADHD
6 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 ID (all 3 cases); ASD and ADHD (1/3 cases)
7 Support Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Pinto D , et al. (2014) Yes -
8 Recent Recommendation CHD2 haploinsufficiency is associated with developmental delay, intellectual disability, epilepsy and neurobehavioural problems. Chnier S , et al. (2014) No ASD (1 case), TS (1 case), ADHD (1 case)
9 Support De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder. Dong S , et al. (2014) No -
10 Support De novo mutations in moderate or severe intellectual disability. Hamdan FF , et al. (2014) No Microcephaly
11 Support Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
12 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
13 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
14 Recent recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
15 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Lelieveld SH , et al. (2016) No -
16 Support Genome-wide characteristics of de novo mutations in autism. Yuen RK , et al. (2016) Yes -
17 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
18 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Trujillano D , et al. (2016) No -
19 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Stessman HA , et al. (2017) Yes -
20 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
21 Positive association De Novo Coding Variants Are Strongly Associated with Tourette Disorder. Willsey AJ , et al. (2017) No -
22 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) Yes ADHD, OCD
Rare Variants   (39)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - Simplex 22178256 Capelli LP , et al. (2011)
c.2567A>G p.Asp856Gly missense_variant De novo - Simplex 22495311 Neale BM , et al. (2012)
c.1809del p.Thr604LeufsTer19 frameshift_variant De novo - Simplex 23020937 Rauch A , et al. (2012)
- p.Glu1412GlyfsTer64 frameshift_variant De novo - - 23708187 Carvill GL , et al. (2013)
- p.Arg121Ter stop_gained De novo - - 23708187 Carvill GL , et al. (2013)
- p.Gly491ValfsTer13 frameshift_variant De novo - - 23708187 Carvill GL , et al. (2013)
- p.Arg1644LysfsTer22 frameshift_variant De novo - - 23708187 Carvill GL , et al. (2013)
- 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.1502+1G>A - splice_site_variant De novo - - 23934111 Epi4K Consortium , et al. (2013)
c.1810-2A>C - splice_site_variant De novo - - 24207121 Suls A , et al. (2013)
c.4971G>A p.Trp1657Ter stop_gained De novo - - 24207121 Suls A , et al. (2013)
c.1396C>T p.Arg466Ter stop_gained De novo - - 24207121 Suls A , et al. (2013)
- - copy_number_loss De novo - Multiplex 24768552 Pinto D , et al. (2014)
- - copy_number_loss De novo - - 24834135 Chnier S , et al. (2014)
- - copy_number_loss De novo - - 24834135 Chnier S , et al. (2014)
- - copy_number_loss De novo - - 24834135 Chnier S , et al. (2014)
- - copy_number_loss De novo - - 24834135 Chnier S , et al. (2014)
delAAAG - frameshift_variant De novo - Simplex 25284784 Dong S , et al. (2014)
c.335C>G p.Ser112Ter stop_gained De novo - Simplex 25356899 Hamdan FF , et al. (2014)
c.3521G>A p.Gly1174Asp missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.2999G>A p.Arg1000Gln missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
ins(G) - frameshift_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.4909C>T p.Arg1637Ter stop_gained De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.373_389​delAACCTTCACCCTCAGAA​insA p.Asn125SerfsTer? frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1942C>T p.Pro648Ser missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.2699G>A p.Arg900Gln missense_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
c.1903_1906del p.Asp635fs frameshift_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
G>A - 3_prime_UTR_variant De novo - Simplex 27525107 Yuen RK , et al. (2016)
c.5054G>A p.Arg1685His missense_variant De novo - - 27824329 Wang T , et al. (2016)
c.2068C>T p.His690Tyr missense_variant De novo - - 27848944 Trujillano D , et al. (2016)
c.4459G>A p.Asp1487Asn missense_variant De novo - Simplex 28191889 Stessman HA , et al. (2017)
c.2693G>A p.Arg898Gln missense_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.4915C>T p.Gln1639Ter stop_gained De novo - - 28191889 Stessman HA , et al. (2017)
c.4216A>G p.Ser1406Gly missense_variant De novo - Multiplex 28263302 C Yuen RK , et al. (2017)
c.2716C>T p.Gln906Ter stop_gained Unknown - Simplex 28263302 C Yuen RK , et al. (2017)
c.1566C>G p.Phe522Leu missense_variant De novo - Simplex 28472652 Willsey AJ , et al. (2017)
c.1551delC p.Gln518Argfs frameshift_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.3787dupG p.Val1263Glyfs frameshift_variant De novo - - 28554332 Bowling KM , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

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).

2

Strong Candidate

See all Category 2 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.

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."

04-01-2017
2S

Initial score established: 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
[The contribution of de novo coding mutations to autism spectrum disorder.2014] [Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017] [Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.2014] [De novo mutations in moderate or severe intellectual disability.2014] [Genome-wide characteristics of de novo mutations in autism.2016] [De novo mutations in epileptic encephalopathies.2013] [Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017] [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] [De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder.2014] [De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome.2013] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [De Novo Coding Variants Are Strongly Associated with Tourette Disorder.2017] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability.2016] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.2017] [Deletion of the RMGA and CHD2 genes in a child with epilepsy and mental deficiency.2011]
CNVs associated with CHD2(1 CNVs)
15q26.1 21 Deletion-Duplication 37  /  95
Animal Models associated with CHD2(2 Models)
CHD2_1_KO_HM Genetic
CHD2_1_KO_HT Genetic
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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