Human Gene Module / Chromosome 5 / CHD1

CHD1chromodomain helicase DNA binding protein 1

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
11 / 14
Rare Variants / Common Variants
21 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
5q15-q21.1
Associated Disorders
ID, ASD, EPS
Relevance to Autism

A de novo damaging missense variant and a de novo frameshift variant in the CHD1 gene have been identified in ASD probands from the Autism Sequencing Consortium and the Simons Simplex Collection (Neale et al., 2012; Iossifov et al., 2014). Pilarowski et al., 2017 described six patients with heterozygous CHD1 missense variants; two of these patients were diagnosed with autism.

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.ATP-dependent chromatin-remodeling factor which functions as substrate recognition component of the transcription regulatory histone acetylation (HAT) complex SAGA. Regulates polymerase II transcription. Also required for efficient transcription by RNA polymerase I, and more specifically the polymerase I transcription termination step. Regulates negatively DNA replication. Not only involved in transcription-related chromatin-remodeling, but also required to maintain a specific chromatin configuration across the genome. Is also associated with histone deacetylase (HDAC) activity

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CHD1 (14 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Patterns and rates of exonic de novo mutations in autism spectrum disorders Neale BM , et al. (2012) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support Recurrent de novo mutations implicate novel genes underlying simplex autism risk O'Roak BJ , et al. (2014) Yes -
4 Recent Recommendation Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability Pilarowski GO , et al. (2017) No ASD, ID, epilepsy/seizures
5 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
6 Support - Mahjani B et al. (2021) Yes -
7 Support - Li D et al. (2022) Yes -
8 Support - Zhou X et al. (2022) Yes -
9 Support - Li S et al. (2023) No -
10 Support - Hu C et al. (2023) Yes -
11 Support - Sheth F et al. (2023) Yes DD, ID
12 Support - Ana Karen Sandoval-Talamantes et al. (2023) Yes -
13 Recent Recommendation - Kuokuo Li et al. (2024) Yes -
14 Support - Axel Schmidt et al. (2024) No ID
Rare Variants   (21)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2569-11A>G - intron_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.13_14del p.Ser5Ter frameshift_variant Unknown - - 34968013 Li D et al. (2022)
c.5069C>A p.Pro1690Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.990C>T p.Asn330%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.2157T>A p.Ser719Arg missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.472T>C p.Ser158Pro missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.5113T>C p.Ser1705Pro missense_variant De novo - Simplex 36625521 Li S et al. (2023)
c.1241A>G p.Gln414Arg missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.2092G>A p.Val698Ile missense_variant Familial Paternal - 37007974 Hu C et al. (2023)
c.258T>C p.Phe86%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.4886C>G p.Ser1629Cys missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.421A>G p.Arg141Gly missense_variant Unknown - - 28866611 Pilarowski GO , et al. (2017)
c.1379G>A p.Arg460Lys missense_variant De novo - - 28866611 Pilarowski GO , et al. (2017)
c.1853G>A p.Arg618Gln missense_variant De novo - - 28866611 Pilarowski GO , et al. (2017)
c.2570A>G p.Asp857Gly missense_variant De novo - - 28866611 Pilarowski GO , et al. (2017)
c.3046C>G p.Leu1016Val missense_variant De novo - Simplex 22495311 Neale BM , et al. (2012)
c.3608G>A p.Arg1203Gln missense_variant De novo - Simplex 25418537 O'Roak BJ , et al. (2014)
c.4757G>A p.Arg1586His missense_variant Familial Paternal Simplex 37543562 Sheth F et al. (2023)
c.5123G>A p.Arg1708Gln missense_variant Unknown - Multiplex 28866611 Pilarowski GO , et al. (2017)
c.4550dup p.Leu1517PhefsTer7 frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.315G>C p.Gln105His missense_variant Unknown - - 38003033 Ana Karen Sandoval-Talamantes et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

A de novo damaging missense variant and a de novo frameshift variant in the CHD1 gene have been identified in ASD probands from the Autism Sequencing Consortium and the Simons Simplex Collection (Neale et al., 2012; Iossifov et al., 2014). Pilarowski et al., 2017 described six patients with heterozygous CHD1 missense variants; two of these patients were diagnosed with autism.

Score Delta: Score remained at 2S

criteria met
See SFARI Gene'scoring criteria
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.

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."

4/1/2022
3S
icon
2S

Decreased from 3S to 2S

Description

A de novo damaging missense variant and a de novo frameshift variant in the CHD1 gene have been identified in ASD probands from the Autism Sequencing Consortium and the Simons Simplex Collection (Neale et al., 2012; Iossifov et al., 2014). Pilarowski et al., 2017 described six patients with heterozygous CHD1 missense variants; two of these patients were diagnosed with autism.

10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

A de novo damaging missense variant and a de novo frameshift variant in the CHD1 gene have been identified in ASD probands from the Autism Sequencing Consortium and the Simons Simplex Collection (Neale et al., 2012; Iossifov et al., 2014). Pilarowski et al., 2017 described six patients with heterozygous CHD1 missense variants; two of these patients were diagnosed with autism.

Reports Added
[New Scoring Scheme]
10/1/2017
icon
4S

Increased from to 4S

Description

A de novo damaging missense variant and a de novo frameshift variant in the CHD1 gene have been identified in ASD probands from the Autism Sequencing Consortium and the Simons Simplex Collection (Neale et al., 2012; Iossifov et al., 2014). Pilarowski et al., 2017 described six patients with heterozygous CHD1 missense variants; two of these patients were diagnosed with autism.

Krishnan Probability Score

Score 0.49468564801236

Ranking 3492/25841 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 0.99999999936286

Ranking 93/18225 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
Sanders TADA Score

Score 0.17156909074973

Ranking 96/18665 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
Zhang D Score

Score 0.56077581741505

Ranking 207/20870 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
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