Human Gene Module / Chromosome 17 / CHD3

CHD3chromodomain helicase DNA binding protein 3

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
7 / 10
Rare Variants / Common Variants
54 / 0
Aliases
CHD3, Mi-2a,  Mi2-ALPHA,  ZFH
Associated Syndromes
Snijders Blok-Campeau syndrome (SNIBCPS), Snijders Blok-Campeau syndrome, ASD, DD, ID
Chromosome Band
17p13.1
Associated Disorders
ASD
Relevance to Autism

Two de novo missense variants and one de novo in-frame deletion variant were identified in the CHD3 gene in ASD probands following whole-exome or whole-genome sequencing (Iossifov et al., 2014; Yuen et al., 2016; Yuen et al., 2017). Snijders Blok et al., 2018 described a cohort of 35 individuals with de novo CHD3 mutations and overlapping phenotypes, including developmental delay/intellectual disability and speech delay/disorder; nine individuals (29%) displayed autism or autistic features, including stereotypic and hand-flapping behavior.

Molecular Function

This gene encodes 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. This protein is one of the components of a histone deacetylase complex referred to as the Mi-2/NuRD complex which participates in the remodeling of chromatin by deacetylating histones. Chromatin remodeling is essential for many processes including transcription.

Reports related to CHD3 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Genome-wide characteristics of de novo mutations in autism Yuen RK et al. (2016) Yes -
3 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
4 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
5 Recent Recommendation CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language Snijders Blok L , et al. (2018) No ASD or autistic features
6 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
7 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
8 Recent Recommendation A second cohort of CHD3 patients expands the molecular mechanisms known to cause Snijders Blok-Campeau syndrome Drivas TG et al. (2020) No Autistic features
9 Recent recommendation - Sadler B et al. (2021) No -
10 Support - Mizukami M et al. (2021) Yes -
Rare Variants   (54)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo NA Simplex 32483341 Drivas TG et al. (2020)
- - copy_number_gain Unknown - Multiplex 32483341 Drivas TG et al. (2020)
- p.Glu315Lys missense_variant De novo NA Simplex 28714951 Lim ET , et al. (2017)
c.1796G>A p.Arg599His missense_variant De novo NA - 31452935 Feliciano P et al. (2019)
c.2902C>G p.Leu968Val missense_variant De novo NA Simplex 27525107 Yuen RK et al. (2016)
c.4073-3_4078del - splice_site_variant De novo NA Simplex 32483341 Drivas TG et al. (2020)
c.2657A>G p.His886Arg missense_variant De novo NA Simplex 32483341 Drivas TG et al. (2020)
c.2749A>T p.Asn917Tyr missense_variant De novo NA Simplex 32483341 Drivas TG et al. (2020)
c.2831T>A p.Phe944Tyr missense_variant De novo NA Simplex 32483341 Drivas TG et al. (2020)
c.2842T>C p.Ser948Pro missense_variant De novo NA Simplex 32483341 Drivas TG et al. (2020)
c.2896C>T p.Arg966Trp missense_variant De novo NA Simplex 32483341 Drivas TG et al. (2020)
c.2897G>C p.Arg966Pro missense_variant De novo NA Simplex 32483341 Drivas TG et al. (2020)
c.2905A>G p.Lys969Glu missense_variant De novo NA Simplex 32483341 Drivas TG et al. (2020)
c.3073C>T p.Arg1025Trp missense_variant De novo NA Simplex 32483341 Drivas TG et al. (2020)
c.3239T>A p.Leu1080His missense_variant De novo NA Simplex 32483341 Drivas TG et al. (2020)
c.3515G>A p.Arg1172Gln missense_variant De novo NA Simplex 32483341 Drivas TG et al. (2020)
c.3784C>T p.Arg1262Trp missense_variant De novo NA Simplex 32483341 Drivas TG et al. (2020)
c.4243C>T p.Arg1415Cys missense_variant De novo NA Simplex 32483341 Drivas TG et al. (2020)
c.5863G>T p.Ala1955Ser missense_variant De novo NA Simplex 32483341 Drivas TG et al. (2020)
c.2896C>T p.Arg966Trp missense_variant De novo NA Simplex 33358638 Mizukami M et al. (2021)
c.4073-2A>G - splice_site_variant De novo NA Simplex 30397230 Snijders Blok L , et al. (2018)
c.5452C>T p.Arg1818Trp missense_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.1369G>T p.Glu457Ter stop_gained De novo NA Simplex 30397230 Snijders Blok L , et al. (2018)
c.4280G>A p.Trp1427Ter stop_gained Familial Maternal Simplex 32483341 Drivas TG et al. (2020)
c.3509C>T p.Thr1170Met missense_variant De novo NA Multiplex 31398340 Ruzzo EK , et al. (2019)
c.2284_2286del p.Lys762del inframe_deletion De novo NA Simplex 28263302 C Yuen RK et al. (2017)
c.2953C>T p.Leu985= missense_variant De novo NA Simplex 30397230 Snijders Blok L , et al. (2018)
c.3784_3786del p.Met1262del inframe_deletion De novo NA Simplex 32483341 Drivas TG et al. (2020)
c.3477C>A p.Gly1159= missense_variant De novo NA Simplex 30397230 Snijders Blok L , et al. (2018)
c.1384del p.Cys462AlafsTer22 frameshift_variant Unknown - Simplex 32483341 Drivas TG et al. (2020)
c.1795dup p.Arg599ProfsTer47 frameshift_variant Unknown - Simplex 32483341 Drivas TG et al. (2020)
c.2657A>G p.His886Arg missense_variant De novo NA Simplex 30397230 Snijders Blok L , et al. (2018)
c.2745G>T p.Leu915Phe missense_variant De novo NA Simplex 30397230 Snijders Blok L , et al. (2018)
c.2761G>A p.Glu921Lys missense_variant De novo NA Simplex 30397230 Snijders Blok L , et al. (2018)
c.2882G>A p.Gly961Glu missense_variant De novo NA Simplex 30397230 Snijders Blok L , et al. (2018)
c.2954G>A p.Arg985Gln missense_variant De novo NA Simplex 30397230 Snijders Blok L , et al. (2018)
c.3362G>C p.Arg1121Pro missense_variant De novo NA Simplex 30397230 Snijders Blok L , et al. (2018)
c.3407C>T p.Thr1136Ile missense_variant De novo NA Simplex 30397230 Snijders Blok L , et al. (2018)
c.3472T>C p.Trp1158Arg missense_variant De novo NA Simplex 30397230 Snijders Blok L , et al. (2018)
c.3505C>T p.Arg1169Trp missense_variant De novo NA Simplex 30397230 Snijders Blok L , et al. (2018)
c.3512A>G p.His1171Arg missense_variant De novo NA Simplex 30397230 Snijders Blok L , et al. (2018)
c.3515G>A p.Arg1172Gln missense_variant De novo NA Simplex 30397230 Snijders Blok L , et al. (2018)
c.3560G>C p.Arg1187Pro missense_variant De novo NA Simplex 30397230 Snijders Blok L , et al. (2018)
c.3707T>C p.Leu1236Pro missense_variant De novo NA Simplex 30397230 Snijders Blok L , et al. (2018)
c.4025G>A p.Arg1342Gln missense_variant De novo NA Simplex 30397230 Snijders Blok L , et al. (2018)
c.5642G>T p.Arg1881Leu missense_variant De novo NA Simplex 30397230 Snijders Blok L , et al. (2018)
c.4532_4535del p.Phe1511TrpfsTer31 frameshift_variant De novo NA - 31452935 Feliciano P et al. (2019)
c.3325_3327del p.Tyr1109del inframe_deletion De novo NA Simplex 30397230 Snijders Blok L , et al. (2018)
c.3357_3358inv p.Lys1120Gln missense_variant De novo NA Simplex 30397230 Snijders Blok L , et al. (2018)
c.5767+33_5767+34insAACG - frameshift_variant De novo NA Simplex 30397230 Snijders Blok L , et al. (2018)
c.3603_3614del p.Met1202_Thr1205del inframe_deletion De novo NA Simplex 32483341 Drivas TG et al. (2020)
c.2953C>T p.Leu985= missense_variant Familial Maternal Multiplex 30397230 Snijders Blok L , et al. (2018)
c.1706A>G p.Gln569Arg missense_variant De novo NA Multiplex (monozygotic twins) 32483341 Drivas TG et al. (2020)
c.3482A>G p.Lys1161Arg missense_variant De novo NA Multiplex (monozygotic twins) 30397230 Snijders Blok L , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Two de novo missense variants and one de novo in-frame deletion variant were identified in the CHD3 gene in ASD probands following whole-exome or whole-genome sequencing (Iossifov et al., 2014; Yuen et al., 2016; Yuen et al., 2017). Snijders Blok et al., 2018 described a cohort of 35 individuals with de novo CHD3 mutations and overlapping phenotypes, including developmental delay/intellectual disability and speech delay/disorder; nine individuals (29%) displayed autism or autistic features, including stereotypic and hand-flapping behavior.

Score Delta: Decreased from 4S to 1

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.

10/1/2021
4S
icon
1

Decreased from 4S to 1

Description

Two de novo missense variants and one de novo in-frame deletion variant were identified in the CHD3 gene in ASD probands following whole-exome or whole-genome sequencing (Iossifov et al., 2014; Yuen et al., 2016; Yuen et al., 2017). Snijders Blok et al., 2018 described a cohort of 35 individuals with de novo CHD3 mutations and overlapping phenotypes, including developmental delay/intellectual disability and speech delay/disorder; nine individuals (29%) displayed autism or autistic features, including stereotypic and hand-flapping behavior.

7/1/2021
4S
icon
1

Decreased from 4S to 1

Description

Two de novo missense variants and one de novo in-frame deletion variant were identified in the CHD3 gene in ASD probands following whole-exome or whole-genome sequencing (Iossifov et al., 2014; Yuen et al., 2016; Yuen et al., 2017). Snijders Blok et al., 2018 described a cohort of 35 individuals with de novo CHD3 mutations and overlapping phenotypes, including developmental delay/intellectual disability and speech delay/disorder; nine individuals (29%) displayed autism or autistic features, including stereotypic and hand-flapping behavior.

4/1/2021
4S
icon
1

Decreased from 4S to 1

Description

Two de novo missense variants and one de novo in-frame deletion variant were identified in the CHD3 gene in ASD probands following whole-exome or whole-genome sequencing (Iossifov et al., 2014; Yuen et al., 2016; Yuen et al., 2017). Snijders Blok et al., 2018 described a cohort of 35 individuals with de novo CHD3 mutations and overlapping phenotypes, including developmental delay/intellectual disability and speech delay/disorder; nine individuals (29%) displayed autism or autistic features, including stereotypic and hand-flapping behavior.

1/1/2021
4S
icon
1

Decreased from 4S to 1

Description

Two de novo missense variants and one de novo in-frame deletion variant were identified in the CHD3 gene in ASD probands following whole-exome or whole-genome sequencing (Iossifov et al., 2014; Yuen et al., 2016; Yuen et al., 2017). Snijders Blok et al., 2018 described a cohort of 35 individuals with de novo CHD3 mutations and overlapping phenotypes, including developmental delay/intellectual disability and speech delay/disorder; nine individuals (29%) displayed autism or autistic features, including stereotypic and hand-flapping behavior.

10/1/2020
4S
icon
1

Decreased from 4S to 1

Description

Two de novo missense variants and one de novo in-frame deletion variant were identified in the CHD3 gene in ASD probands following whole-exome or whole-genome sequencing (Iossifov et al., 2014; Yuen et al., 2016; Yuen et al., 2017). Snijders Blok et al., 2018 described a cohort of 35 individuals with de novo CHD3 mutations and overlapping phenotypes, including developmental delay/intellectual disability and speech delay/disorder; nine individuals (29%) displayed autism or autistic features, including stereotypic and hand-flapping behavior.

7/1/2020
4S
icon
1

Decreased from 4S to 1

Description

Two de novo missense variants and one de novo in-frame deletion variant were identified in the CHD3 gene in ASD probands following whole-exome or whole-genome sequencing (Iossifov et al., 2014; Yuen et al., 2016; Yuen et al., 2017). Snijders Blok et al., 2018 described a cohort of 35 individuals with de novo CHD3 mutations and overlapping phenotypes, including developmental delay/intellectual disability and speech delay/disorder; nine individuals (29%) displayed autism or autistic features, including stereotypic and hand-flapping behavior.

4/1/2020
4S
icon
1

Decreased from 4S to 1

Description

Two de novo missense variants and one de novo in-frame deletion variant were identified in the CHD3 gene in ASD probands following whole-exome or whole-genome sequencing (Iossifov et al., 2014; Yuen et al., 2016; Yuen et al., 2017). Snijders Blok et al., 2018 described a cohort of 35 individuals with de novo CHD3 mutations and overlapping phenotypes, including developmental delay/intellectual disability and speech delay/disorder; nine individuals (29%) displayed autism or autistic features, including stereotypic and hand-flapping behavior.

1/1/2020
4S
icon
1

Decreased from 4S to 1

Description

Two de novo missense variants and one de novo in-frame deletion variant were identified in the CHD3 gene in ASD probands following whole-exome or whole-genome sequencing (Iossifov et al., 2014; Yuen et al., 2016; Yuen et al., 2017). Snijders Blok et al., 2018 described a cohort of 35 individuals with de novo CHD3 mutations and overlapping phenotypes, including developmental delay/intellectual disability and speech delay/disorder; nine individuals (29%) displayed autism or autistic features, including stereotypic and hand-flapping behavior.

10/1/2019
4S
icon
1

Decreased from 4S to 1

New Scoring Scheme
Description

Two de novo missense variants and one de novo in-frame deletion variant were identified in the CHD3 gene in ASD probands following whole-exome or whole-genome sequencing (Iossifov et al., 2014; Yuen et al., 2016; Yuen et al., 2017). Snijders Blok et al., 2018 described a cohort of 35 individuals with de novo CHD3 mutations and overlapping phenotypes, including developmental delay/intellectual disability and speech delay/disorder; nine individuals (29%) displayed autism or autistic features, including stereotypic and hand-flapping behavior.

7/1/2019
4S
icon
1

Decreased from 4S to 1

Description

Two de novo missense variants and one de novo in-frame deletion variant were identified in the CHD3 gene in ASD probands following whole-exome or whole-genome sequencing (Iossifov et al., 2014; Yuen et al., 2016; Yuen et al., 2017). Snijders Blok et al., 2018 described a cohort of 35 individuals with de novo CHD3 mutations and overlapping phenotypes, including developmental delay/intellectual disability and speech delay/disorder; nine individuals (29%) displayed autism or autistic features, including stereotypic and hand-flapping behavior.

4/1/2019
4S
icon
1

Decreased from 4S to 1

Description

Two de novo missense variants and one de novo in-frame deletion variant were identified in the CHD3 gene in ASD probands following whole-exome or whole-genome sequencing (Iossifov et al., 2014; Yuen et al., 2016; Yuen et al., 2017). Snijders Blok et al., 2018 described a cohort of 35 individuals with de novo CHD3 mutations and overlapping phenotypes, including developmental delay/intellectual disability and speech delay/disorder; nine individuals (29%) displayed autism or autistic features, including stereotypic and hand-flapping behavior.

1/1/2019
4S
icon
1

Decreased from 4S to 1

Description

Two de novo missense variants and one de novo in-frame deletion variant were identified in the CHD3 gene in ASD probands following whole-exome or whole-genome sequencing (Iossifov et al., 2014; Yuen et al., 2016; Yuen et al., 2017). Snijders Blok et al., 2018 described a cohort of 35 individuals with de novo CHD3 mutations and overlapping phenotypes, including developmental delay/intellectual disability and speech delay/disorder; nine individuals (29%) displayed autism or autistic features, including stereotypic and hand-flapping behavior.

10/1/2018
icon
1

Increased from to 1

Description

Two de novo missense variants and one de novo in-frame deletion variant were identified in the CHD3 gene in ASD probands following whole-exome or whole-genome sequencing (Iossifov et al., 2014; Yuen et al., 2016; Yuen et al., 2017). Snijders Blok et al., 2018 described a cohort of 35 individuals with de novo CHD3 mutations and overlapping phenotypes, including developmental delay/intellectual disability and speech delay/disorder; nine individuals (29%) displayed autism or autistic features, including stereotypic and hand-flapping behavior.

Krishnan Probability Score

Score 0.50356225951409

Ranking 1941/25841 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.
ExAC Score

Score 0.99999999551797

Ranking 123/18225 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
Sanders TADA Score

Score 0.90096203965782

Ranking 6477/18665 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).
Zhang D Score

Score 0.50767055769192

Ranking 472/20870 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.
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