Human Gene Module / Chromosome 21 / DSCAM

DSCAMDown syndrome cell adhesion molecule

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
10 / 11
Rare Variants / Common Variants
21 / 3
Aliases
DSCAM, CHD2,  CHD2-42,  CHD2-52
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Genetic Association
Chromosome Band
21q22.2
Associated Disorders
ASD
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).

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)

Reports related to DSCAM (11 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 ... 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 Positive Association Clustering by phenotype and genome-wide association study in autism Narita A et al. (2020) Yes ASD sub-phenotype
Rare Variants   (21)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.4885C>T p.Arg1629Ter stop_gained De novo NA - 27824329 Wang T , et al. (2016)
- - copy_number_loss Familial Maternal Simplex 26749308 Turner TN et al. (2016)
c.596C>T p.Thr199Met missense_variant Unknown - - 27824329 Wang T , et al. (2016)
c.2356+2T>G - splice_site_variant De novo NA - 25363760 De Rubeis S , et al. (2014)
c.4420G>T p.Glu1474Ter stop_gained Familial Maternal - 27824329 Wang T , et al. (2016)
c.4132+2T>A - splice_site_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.3563-12C>G - intron_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.3696+50C>T - intron_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.596C>T p.Thr199Met missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.3253G>A p.Glu1085Lys missense_variant De novo NA Simplex 30564305 Guo H , et al. (2018)
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.1067del p.Pro356LeufsTer5 frameshift_variant De novo NA - 27824329 Wang T , et al. (2016)
c.4859G>A p.Arg1620Gln missense_variant Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.1163G>T p.Arg388Leu missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.4024G>A p.Gly1342Arg missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.5653dup p.Met1885AsnfsTer82 frameshift_variant De novo NA - 28191889 Stessman HA , et al. (2017)
c.5653dup p.Met1885AsnfsTer82 frameshift_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.4020_4021insTA p.Asn1341Ter frameshift_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.4019_4020insTA p.Asn1341ThrfsTer10 frameshift_variant De novo NA - 28191889 Stessman HA , et al. (2017)
c.1533_1537del p.Lys511AsnfsTer24 frameshift_variant Unknown - Multiplex 28263302 C Yuen RK et al. (2017)
Common Variants   (3)
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)
c.2357-19309A>G - intron_variant - - - 32807774 Narita A et al. (2020)
c.2357-33846G>A - intron_variant - - - 32807774 Narita A et al. (2020)
SFARI Gene score
1

High Confidence

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).

Score Delta: Score remained at 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.

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).

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).

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).

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.

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.

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.

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).

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.
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
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
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).
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.
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.
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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SFARI Gene Update

We are pleased to announce some changes to the ongoing curation of the data in SFARI Gene. In the context of a continued effort to develop the human gene module and its manually curated list of autism risk genes, we are modifying other aspects of the site to focus on the information that is of greatest interest to the research community. The version of SFARI Gene that has been developed until now will be frozen and will remain available as “SFARI Gene Archive”. Please see the announcement for more details.
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