Human Gene Module / Chromosome 21 / DSCAM

DSCAMDown syndrome cell adhesion molecule

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
14 / 18
Rare Variants / Common Variants
80 / 1
EAGLE Score
13.5
Strong Learn More
Aliases
DSCAM, CHD2,  CHD2-42,  CHD2-52
Associated Syndromes
-
Chromosome Band
21q22.2
Associated Disorders
ID
Genetic Category
Rare Single Gene Mutation, Genetic Association, Functional
Relevance to Autism

Three de novo loss-of-function (LoF) variants in the DSCAM gene were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014 (PMID 25363768), while a fourth de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760). Two additional de novo LoF variants were identified in Chinese ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016 (PMID 27824329). Transmission and de novo association (TADA) analyses in Sanders et al., 2015 and Satterstrom et al., 2020 identified DSCAM as a candidate gene with a false discovery rate (FDR) 0.01. An intronic SNP in the DSCAM gene was found to associate with ASD in a GWAS meta-analysis of 7387 ASD cases and 8567 controls with a P-value < 1.0E-04 (Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium 2017). 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 DSCAM as a gene reaching study-wide significance based on 5,754 constraint genes (P < 8.69E-06).

Molecular Function

This gene is a member of the immunoglobulin superfamily of cell adhesion molecules (Ig-CAMs), and is involved in human central and peripheral nervous system development. This gene is a candidate for Down syndrome and congenital heart disease (DSCHD)

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome Informatics
Fruit fly
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to DSCAM (18 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 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
3 Support Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci Sanders SJ , et al. (2015) Yes -
4 Recent Recommendation Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA Turner TN et al. (2016) Yes -
5 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
6 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases Stessman HA , et al. (2017) No -
7 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
8 Positive Association Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017) Yes -
9 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
10 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
11 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes ID
12 Recent Recommendation - Lim CS et al. (2021) Yes -
13 Support - Mahjani B et al. (2021) Yes -
14 Support - Chen P et al. (2021) Yes -
15 Support - Yang T et al. (2022) No -
16 Support - Zhou X et al. (2022) Yes -
17 Support - Spataro N et al. (2023) No Learning disability
18 Support - Ken-Ichi Dewa et al. (2024) No -
Rare Variants   (80)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.4919+1G>T - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.1504A>T p.Arg502Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.4420G>T p.Glu1474Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
n.813+1G>A p.? splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.4885C>T p.Arg1629Ter stop_gained De novo - - 27824329 Wang T , et al. (2016)
c.386G>A p.Arg129His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.412G>A p.Gly138Ser missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.587G>A p.Arg196His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.598C>T p.Arg200Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.928G>A p.Val310Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4744C>T p.Gln1582Ter stop_gained Unknown - - 34615535 Mahjani B et al. (2021)
- - copy_number_loss Familial Maternal Simplex 26749308 Turner TN et al. (2016)
c.1162C>T p.Arg388Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1288G>A p.Val430Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1400G>T p.Ser467Ile missense_variant De novo - - 33004838 Wang T et al. (2020)
c.1903C>T p.Arg635Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2089C>T p.Arg697Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2458C>T p.Arg820Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2459G>A p.Arg820His missense_variant De novo - - 33004838 Wang T et al. (2020)
c.2501G>A p.Arg834His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2624G>A p.Arg875His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2695C>T p.Arg899Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2386A>G p.Thr796Ala missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.596C>T p.Thr199Met missense_variant Unknown - - 27824329 Wang T , et al. (2016)
c.2356+2T>G - splice_site_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.3121G>T p.Asp1041Tyr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3130G>T p.Gly1044Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3511G>A p.Ala1171Thr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3547C>T p.Arg1183Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3737A>G p.Tyr1246Cys missense_variant De novo - - 33004838 Wang T et al. (2020)
c.4045G>A p.Val1349Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4474G>A p.Val1492Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4504G>A p.Gly1502Ser missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4645C>T p.Arg1549Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4694C>T p.Thr1565Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4849C>T p.Arg1617Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4943C>T p.Thr1648Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4970G>A p.Arg1657Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5017G>C p.Asp1673His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5041C>T p.Arg1681Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5048C>T p.Thr1683Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5060C>T p.Thr1687Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5102C>T p.Thr1701Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5174G>A p.Arg1725Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5261G>A p.Arg1754Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5387G>T p.Arg1796Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5531C>T p.Ser1844Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5543C>T p.Thr1848Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5680C>G p.Arg1894Gly missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5681G>A p.Arg1894Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4216G>A p.Gly1406Ser missense_variant De novo - - 36980980 Spataro N et al. (2023)
c.4132+2T>A - splice_site_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.3563-12C>G - intron_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.3696+50C>T - intron_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.4420G>T p.Glu1474Ter stop_gained Familial Maternal - 27824329 Wang T , et al. (2016)
c.2458C>T p.Arg820Cys missense_variant Unknown - Simplex 33004838 Wang T et al. (2020)
c.700C>T p.Arg234Cys missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.3253G>A p.Glu1085Lys missense_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.5060C>T p.Thr1687Met missense_variant Unknown - Simplex 33004838 Wang T et al. (2020)
c.5114C>T p.Thr1705Met missense_variant Unknown - Simplex 33004838 Wang T et al. (2020)
c.1009G>A p.Val337Met missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.2051del p.Leu684Ter frameshift_variant De novo - Simplex 34253863 Lim CS et al. (2021)
c.2511G>A p.Val837%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.596C>T p.Thr199Met missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.1067del p.Pro356LeufsTer5 frameshift_variant De novo - - 27824329 Wang T , et al. (2016)
c.5174G>A p.Arg1725Gln missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.5681G>A p.Arg1894Gln missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.5687-1G>A - splice_site_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.4859G>A p.Arg1620Gln missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.1387G>A p.Gly463Arg splice_site_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.4859G>A p.Arg1620Gln missense_variant Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.3375_3376del p.Arg1125SerfsTer14 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.5113_5114del p.Thr1705GlyfsTer148 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1163G>T p.Arg388Leu missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.5653dup p.Met1885AsnfsTer82 frameshift_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.4024G>A p.Gly1342Arg missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.5653dup p.Met1885AsnfsTer82 frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.4020_4021insTA p.Asn1341Ter frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.4019_4020insTA p.Asn1341ThrfsTer10 frameshift_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.1533_1537del p.Lys511AsnfsTer24 frameshift_variant Unknown - Multiplex 28263302 C Yuen RK et al. (2017)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.3851-2266A>G;c.3143-2266A>G - intron_variant - - - 28540026 Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017)
SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

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.

7/1/2020
1
icon
1

Score remained at 1

Description

Three de novo loss-of-function (LoF) variants in the DSCAM gene were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014 (PMID 25363768), while a fourth de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760). Two additional de novo LoF variants were identified in Chinese ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016 (PMID 27824329).

Reports Added
[Clustering by phenotype and genome-wide association study in autism2020]
1/1/2020
1
icon
1

Score remained at 1

Description

Three de novo loss-of-function (LoF) variants in the DSCAM gene were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014 (PMID 25363768), while a fourth de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760). Two additional de novo LoF variants were identified in Chinese ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016 (PMID 27824329).

Reports Added
[Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.2015] [Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
1
icon
1

Score remained at 1

New Scoring Scheme
Description

Three de novo loss-of-function (LoF) variants in the DSCAM gene were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014 (PMID 25363768), while a fourth de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760). Two additional de novo LoF variants were identified in Chinese ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016 (PMID 27824329).

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

Score remained at 1

Description

Three de novo loss-of-function (LoF) variants in the DSCAM gene were identified in ASD probands from the Simons Simplex Collection in Iossifov et al., 2014 (PMID 25363768), while a fourth de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760). Two additional de novo LoF variants were identified in Chinese ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016 (PMID 27824329).

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
4/1/2017
1
icon
1

Score remained at 1

Description

Three de novo LoF variants in the DSCAM gene were identified in ASD probands from the Simons Simplex Collection (PMID 25363768), while a fourth de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Two additional de novo LoF variants were identified in Chinese ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.

Reports Added
[The contribution of de novo coding mutations to autism spectrum disorder2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA2016] [De novo genic mutations among a Chinese autism spectrum disorder cohort.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] [Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with ...2017]
1/1/2017
1
icon
1

Score remained at 1

Description

Three de novo LoF variants in the DSCAM gene were identified in ASD probands from the Simons Simplex Collection (PMID 25363768), while a fourth de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Two additional de novo LoF variants were identified in Chinese ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.

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

Decreased from 2 to 1

Description

Three de novo LoF variants in the DSCAM gene were identified in ASD probands from the Simons Simplex Collection (PMID 25363768), while a fourth de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Two additional de novo LoF variants were identified in Chinese ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.

Reports Added
[De novo genic mutations among a Chinese autism spectrum disorder cohort.2016]
1/1/2016
2
icon
2

Decreased from 2 to 2

Description

Three de novo LoF variants in the DSCAM gene were identified in ASD probands from the Simons Simplex Collection (PMID 25363768), while a fourth de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760).

Reports Added
[The contribution of de novo coding mutations to autism spectrum disorder2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA2016]
10/1/2014
icon
2

Increased from to 2

Description

Three de novo LoF variants in the DSCAM gene were identified in ASD probands from the Simons Simplex Collection (PMID 25363768), while a fourth de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760).

Krishnan Probability Score

Score 0.61055010332687

Ranking 220/25841 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 0.99999999983846

Ranking 77/18225 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 0.999

Ranking 3/239 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 0.00028021804687253

Ranking 16/18665 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 36

Ranking 60/461 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 -0.039883075305906

Ranking 10049/20870 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
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
DCC Netrin receptor DCC Mouse Protein Binding 13176 P70211
LGR4 leucine-rich repeat containing G protein-coupled receptor 4 Human Protein Binding 55366 Q59ER8
Netrin-1 Netrin-1 Mouse Direct Regulation 18208 O09118
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