Human Gene Module / Chromosome 8 / CSMD1

CSMD1CUB and Sushi multiple domains 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
19 / 23
Rare Variants / Common Variants
51 / 3
Aliases
CSMD1, UNQ5952/PRO19863,  PPP1R24
Associated Syndromes
-
Chromosome Band
8p23.2
Associated Disorders
-
Relevance to Autism

Potentially damaging heterozygous missense variants in the CSMD1 gene were identified in affected members of two extended multiplex ASD families (Cukier et al., 2014).

Molecular Function

Weakly expressed in most tissues, except in brain (expressed at intermediate levels in brain, including cerebellum, substantia nigra, hippocampus, and fetal brain). Variants in this gene have been shown to associate with schizophrenia and bipolar disorder.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CSMD1 (23 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Positive Association - Bjarte HÃ¥vik et al. (2011) No -
2 Support De novo mutations revealed by whole-exome sequencing are strongly associated with autism Sanders SJ , et al. (2012) Yes -
3 Primary Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders Cukier HN , et al. (2014) Yes -
4 Support Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene panel Brett M , et al. (2014) Yes MCA
5 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
6 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
7 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
8 Positive Association Genome-wide Association Study of Autism Spectrum Disorder in the East Asian Populations Liu X , et al. (2015) Yes -
9 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
10 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases Stessman HA , et al. (2017) Yes -
11 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
12 Positive Association Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection Pardias AF , et al. (2018) No -
13 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes Guo H , et al. (2018) Yes -
14 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
15 Support - Alonso-Gonzalez A et al. (2021) Yes -
16 Support - Woodbury-Smith M et al. (2022) Yes -
17 Support - Zhou X et al. (2022) Yes -
18 Support - Tuncay IO et al. (2023) Yes -
19 Support - Cirnigliaro M et al. (2023) Yes -
20 Support - Sheth F et al. (2023) Yes DD, ID, epilepsy/seizures
21 Support - Matthew L Baum et al. (2024) No -
22 Support - Elizabeth A Werren et al. (2024) No ASD, ADHD, epilepsy/seizures
23 Support - Afif Ben-Mahmoud et al. (2024) Yes DD
Rare Variants   (51)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.86-4C>G - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.292T>A p.Leu98Ile missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.373G>C p.Asp125His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.540C>G p.His180Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1462A>G p.Ser488Gly missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2071A>G p.Thr691Ala missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.7138+2T>C - splice_site_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.3164G>T p.Arg1055Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3972C>G p.Asp1324Glu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4492A>C p.Met1498Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.5146A>T p.Ser1716Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.8392G>A p.Asp2798Asn missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4368G>T p.Thr1456%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.9111T>C p.Cys3037%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.1915G>A p.Ala639Thr missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.2381A>C p.His794Pro missense_variant De novo - Simplex 30504930 Guo H , et al. (2018)
c.10031A>T p.Lys3344Ile missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.3766C>G p.Leu1256Val missense_variant Unknown - Simplex 37543562 Sheth F et al. (2023)
c.5163C>G p.Ala1721= synonymous_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.9111T>C p.Cys3037%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.9324G>A p.Val3108%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.5399T>A p.Val1800Glu missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.3826G>A p.Glu1276Lys missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.3469C>G p.Leu1157Val missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.9868G>A p.Asp3290Asn missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.3688C>T p.Arg1230Cys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.4205G>A p.Arg1402His missense_variant Familial Paternal - 37492102 Tuncay IO et al. (2023)
c.7795C>T p.Leu2599Phe missense_variant Familial Maternal - 37492102 Tuncay IO et al. (2023)
c.6762A>G p.Gln2254Arg missense_variant De novo - Simplex 22495306 Sanders SJ , et al. (2012)
c.8013C>T p.Ser2671%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.7285+2T>C - splice_site_variant Familial - Simplex 38816421 Elizabeth A Werren et al. (2024)
c.1613G>A p.Arg538Gln missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.2629G>A p.Gly877Ser missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.5185G>C p.Val1729Leu missense_variant Unknown - Simplex 39519104 Afif Ben-Mahmoud et al. (2024)
c.5432G>A p.Gly1811Asp missense_variant Unknown - Simplex 39519104 Afif Ben-Mahmoud et al. (2024)
c.3161G>T p.Ser1054Ile missense_variant De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.412G>A p.Glu138Lys missense_variant Familial - Simplex 38816421 Elizabeth A Werren et al. (2024)
c.638G>T p.Arg213Leu missense_variant Familial - Simplex 38816421 Elizabeth A Werren et al. (2024)
c.4120G>A p.Gly1374Ser missense_variant Familial Paternal Multiplex 24690944 Brett M , et al. (2014)
c.6886G>A p.Asp2296Asn missense_variant Familial - Simplex 38816421 Elizabeth A Werren et al. (2024)
c.7322G>C p.Gly2441Ala missense_variant Familial - Simplex 38816421 Elizabeth A Werren et al. (2024)
c.9424G>A p.Val3142Met missense_variant Familial - Simplex 38816421 Elizabeth A Werren et al. (2024)
c.1507C>A p.His503Asn missense_variant Familial Maternal Simplex 38816421 Elizabeth A Werren et al. (2024)
c.8850C>G p.His2950Gln missense_variant Familial Paternal Simplex 38816421 Elizabeth A Werren et al. (2024)
c.559G>A p.Val187Ile missense_variant Familial Both parents Simplex 38816421 Elizabeth A Werren et al. (2024)
c.4920C>A p.Asn1640Lys missense_variant Familial Paternal Multiplex 38816421 Elizabeth A Werren et al. (2024)
c.6762G>C p.Gln2254His missense_variant Familial Maternal Multiplex 38816421 Elizabeth A Werren et al. (2024)
c.6913del p.Gln2305SerfsTer84 frameshift_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.5852C>T p.Ser1951Phe missense_variant Familial Both parents Multiplex 38816421 Elizabeth A Werren et al. (2024)
c.2480G>A p.Gly827Asp missense_variant Familial - Extended multiplex (at least one pair of ASD affec 24410847 Cukier HN , et al. (2014)
c.6784C>G p.Pro2262Ala missense_variant Familial - Extended multiplex (at least one pair of ASD affec 24410847 Cukier HN , et al. (2014)
Common Variants   (3)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- - intergenic_variant - - - 26314684 Liu X , et al. (2015)
c.415+96863_415+96864insT - intron_variant - - - 29483656 Pardias AF , et al. (2018)
c.85+36272C>G;c.85+36272C>A - intron_variant - - - 21439553 Bjarte HÃ¥vik et al. (2011)
SFARI Gene score
2

Strong Candidate

Potentially damaging heterozygous missense variants in the CSMD1 gene were identified in affected members of two extended multiplex ASD families (Cukier et al., 2014). De novo missense variants in this gene, several of which were predicted to be damaging, have been identified in ASD probands from the Simons Simplex Collection (Sanders et al., 2012; Iossifov et al., 2012; Iossifov et al., 2014) and the Autism Sequencing Consortium (De Rubeis et al., 2014), while a de novo loss-of-function variant in CSMD1 was observed in an ASD proband from the Autism Genetic Resource Exchange in Stessman et al., 2017. A maternally-inherited CSMD1 missense variant that was not present in dbSNP and was predicted to be damaging (CADD score 34) was observed in two unrelated probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016. A SNP upstream of the CSMD1 gene (rs2733052, minor allele C) associated with ASD in a case-control analysis of Japanese ASD cases and controls (P-value 9.49E-06) in Liu et al., 2016.

Score Delta: Score remained at 2

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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Potentially damaging heterozygous missense variants in the CSMD1 gene were identified in affected members of two extended multiplex ASD families (Cukier et al., 2014). De novo missense variants in this gene, several of which were predicted to be damaging, have been identified in ASD probands from the Simons Simplex Collection (Sanders et al., 2012; Iossifov et al., 2012; Iossifov et al., 2014) and the Autism Sequencing Consortium (De Rubeis et al., 2014), while a de novo loss-of-function variant in CSMD1 was observed in an ASD proband from the Autism Genetic Resource Exchange in Stessman et al., 2017. A maternally-inherited CSMD1 missense variant that was not present in dbSNP and was predicted to be damaging (CADD score 34) was observed in two unrelated probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016. A SNP upstream of the CSMD1 gene (rs2733052, minor allele C) associated with ASD in a case-control analysis of Japanese ASD cases and controls (P-value 9.49E-06) in Liu et al., 2016.

1/1/2021
3
icon
3

Decreased from 3 to 3

Description

Potentially damaging heterozygous missense variants in the CSMD1 gene were identified in affected members of two extended multiplex ASD families (Cukier et al., 2014). De novo missense variants in this gene, several of which were predicted to be damaging, have been identified in ASD probands from the Simons Simplex Collection (Sanders et al., 2012; Iossifov et al., 2012; Iossifov et al., 2014) and the Autism Sequencing Consortium (De Rubeis et al., 2014), while a de novo loss-of-function variant in CSMD1 was observed in an ASD proband from the Autism Genetic Resource Exchange in Stessman et al., 2017. A maternally-inherited CSMD1 missense variant that was not present in dbSNP and was predicted to be damaging (CADD score 34) was observed in two unrelated probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016. A SNP upstream of the CSMD1 gene (rs2733052, minor allele C) associated with ASD in a case-control analysis of Japanese ASD cases and controls (P-value 9.49E-06) in Liu et al., 2016.

Reports Added
[Exploring the biological role of postzygotic and germinal de novo mutations in ASD2021]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Potentially damaging heterozygous missense variants in the CSMD1 gene were identified in affected members of two extended multiplex ASD families (Cukier et al., 2014). De novo missense variants in this gene, several of which were predicted to be damaging, have been identified in ASD probands from the Simons Simplex Collection (Sanders et al., 2012; Iossifov et al., 2012; Iossifov et al., 2014) and the Autism Sequencing Consortium (De Rubeis et al., 2014), while a de novo loss-of-function variant in CSMD1 was observed in an ASD proband from the Autism Genetic Resource Exchange in Stessman et al., 2017. A maternally-inherited CSMD1 missense variant that was not present in dbSNP and was predicted to be damaging (CADD score 34) was observed in two unrelated probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016. A SNP upstream of the CSMD1 gene (rs2733052, minor allele C) associated with ASD in a case-control analysis of Japanese ASD cases and controls (P-value 9.49E-06) in Liu et al., 2016.

Reports Added
[New Scoring Scheme]
1/1/2019
4
icon
4

Decreased from 4 to 4

Description

Potentially damaging heterozygous missense variants in the CSMD1 gene were identified in affected members of two extended multiplex ASD families (Cukier et al., 2014). De novo missense variants in this gene, several of which were predicted to be damaging, have been identified in ASD probands from the Simons Simplex Collection (Sanders et al., 2012; Iossifov et al., 2012; Iossifov et al., 2014) and the Autism Sequencing Consortium (De Rubeis et al., 2014), while a de novo loss-of-function variant in CSMD1 was observed in an ASD proband from the Autism Genetic Resource Exchange in Stessman et al., 2017. A maternally-inherited CSMD1 missense variant that was not present in dbSNP and was predicted to be damaging (CADD score 34) was observed in two unrelated probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016. A SNP upstream of the CSMD1 gene (rs2733052, minor allele C) associated with ASD in a case-control analysis of Japanese ASD cases and controls (P-value 9.49E-06) in Liu et al., 2016.

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
10/1/2018
4
icon
4

Decreased from 4 to 4

Description

Potentially damaging heterozygous missense variants in the CSMD1 gene were identified in affected members of two extended multiplex ASD families (Cukier et al., 2014). De novo missense variants in this gene, several of which were predicted to be damaging, have been identified in ASD probands from the Simons Simplex Collection (Sanders et al., 2012; Iossifov et al., 2012; Iossifov et al., 2014) and the Autism Sequencing Consortium (De Rubeis et al., 2014), while a de novo loss-of-function variant in CSMD1 was observed in an ASD proband from the Autism Genetic Resource Exchange in Stessman et al., 2017. A maternally-inherited CSMD1 missense variant that was not present in dbSNP and was predicted to be damaging (CADD score 34) was observed in two unrelated probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016. A SNP upstream of the CSMD1 gene (rs2733052, minor allele C) associated with ASD in a case-control analysis of Japanese ASD cases and controls (P-value 9.49E-06) in Liu et al., 2016.

Reports Added
[Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.2018]
7/1/2018
icon
4

Increased from to 4

Description

Potentially damaging heterozygous missense variants in the CSMD1 gene were identified in affected members of two extended multiplex ASD families (Cukier et al., 2014). De novo missense variants in this gene, several of which were predicted to be damaging, have been identified in ASD probands from the Simons Simplex Collection (Sanders et al., 2012; Iossifov et al., 2012; Iossifov et al., 2014) and the Autism Sequencing Consortium (De Rubeis et al., 2014), while a de novo loss-of-function variant in CSMD1 was observed in an ASD proband from the Autism Genetic Resource Exchange in Stessman et al., 2017. A maternally-inherited CSMD1 missense variant that was not present in dbSNP and was predicted to be damaging (CADD score 34) was observed in two unrelated probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016. A SNP upstream of the CSMD1 gene (rs2733052, minor allele C) associated with ASD in a case-control analysis of Japanese ASD cases and controls (P-value 9.49E-06) in Liu et al., 2016.

Krishnan Probability Score

Score 0.50079914921136

Ranking 2061/25841 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
Sanders TADA Score

Score 0.95061820696553

Ranking 18563/18665 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 14

Ranking 136/461 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 -0.019435253171429

Ranking 9334/20870 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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