Human Gene Module / Chromosome 8 / DLGAP2

DLGAP2discs, large (Drosophila) homolog-associated protein 2

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
11 / 14
Rare Variants / Common Variants
25 / 2
Aliases
DLGAP2, DAP2,  SAPAP2
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
8p23.3
Associated Disorders
-
Relevance to Autism

Rare mutations in the DLGAP2 gene have been identified with autism. In separate studies, de novo duplications were found in patients with ASD (Marshall et al., 2008; Pinto et al., 2010).

Molecular Function

The encoded protein is a membrane-associated guanylate kinase localized at the post-synaptic density in neuronal cells.

Reports related to DLGAP2 (14 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Distinct spatiotemporal expression of SAPAP transcripts in the developing rat brain: a novel dendritically localized mRNA. Kindler S , et al. (2004) No -
2 Recent Recommendation Computational and experimental identification of novel human imprinted genes. Luedi PP , et al. (2007) No -
3 Primary Structural variation of chromosomes in autism spectrum disorder. Marshall CR , et al. (2008) Yes -
4 Recent Recommendation Fragile X mental retardation protein regulates the levels of scaffold proteins and glutamate receptors in postsynaptic densities. Schtt J , et al. (2009) No -
5 Support Functional impact of global rare copy number variation in autism spectrum disorders. Pinto D , et al. (2010) Yes -
6 Support Deep exon resequencing of DLGAP2 as a candidate gene of autism spectrum disorders. Chien WH , et al. (2013) Yes -
7 Support Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders. Cukier HN , et al. (2014) Yes -
8 Support Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
9 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
10 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
11 Support Comprehensive molecular testing in patients with high functioning autism spectrum disorder. Alvarez-Mora MI , et al. (2016) Yes -
12 Support Resequencing and Association Analysis of Six PSD-95-Related Genes as Possible Susceptibility Genes for Schizophrenia and Autism Spectrum Disorders. Xing J , et al. (2016) Yes -
13 Support Segregating patterns of copy number variations in extended autism spectrum disorder (ASD) pedigrees Woodbury-Smith M et al. (2020) Yes -
14 Support Next-Generation Sequencing in Korean Children With Autism Spectrum Disorder and Comorbid Epilepsy Lee J et al. (2020) Yes -
Rare Variants   (25)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain Unknown - - 32477112 Lee J et al. (2020)
- - copy_number_gain De novo NA - 20531469 Pinto D , et al. (2010)
- - copy_number_loss Unknown - - 26845707 Alvarez-Mora MI , et al. (2016)
- - copy_number_gain De novo NA Simplex 18252227 Marshall CR , et al. (2008)
c.136G>A p.Gly46Ser missense_variant Unknown - - 27271353 Xing J , et al. (2016)
c.520G>A p.Asp174Asn missense_variant Unknown - - 27271353 Xing J , et al. (2016)
c.371G>T p.Arg124Leu missense_variant Familial - - 27271353 Xing J , et al. (2016)
c.1225A>G p.Ser409Gly missense_variant Unknown - - 27271353 Xing J , et al. (2016)
c.1289C>T p.Ser430Phe missense_variant Unknown - - 27271353 Xing J , et al. (2016)
c.1997G>A p.Ser666Asn missense_variant Unknown - - 27271353 Xing J , et al. (2016)
c.2044G>A p.Ala682Thr missense_variant Unknown - - 27271353 Xing J , et al. (2016)
c.2219C>A p.Thr740Asn missense_variant Unknown - - 27271353 Xing J , et al. (2016)
c.2284G>A p.Val762Ile missense_variant Unknown - - 27271353 Xing J , et al. (2016)
c.637A>G p.Met213Val missense_variant De novo NA - 25363760 De Rubeis S , et al. (2014)
- - copy_number_gain Familial Paternal Multiplex 32372567 Woodbury-Smith M et al. (2020)
c.574G>T p.Ala192Ser missense_variant Unknown - Unknown 23915500 Chien WH , et al. (2013)
c.2216G>C p.Arg739Thr missense_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.44C>T p.Ser15Phe missense_variant Familial Maternal Simplex 23915500 Chien WH , et al. (2013)
c.1810C>T p.Arg604Cys missense_variant Familial Paternal Simplex 27271353 Xing J , et al. (2016)
c.277C>A p.Leu93Met missense_variant Familial Maternal Simplex 23915500 Chien WH , et al. (2013)
c.545G>A p.Gly182Asp missense_variant Familial Paternal Simplex 23915500 Chien WH , et al. (2013)
c.970A>T p.Arg324Trp missense_variant Familial Paternal Simplex 23915500 Chien WH , et al. (2013)
c.1516T>C p.Cys506Arg missense_variant Familial Paternal Simplex 23915500 Chien WH , et al. (2013)
c.2392G>C p.Glu798Gln missense_variant Familial Maternal Simplex 23915500 Chien WH , et al. (2013)
c.2209G>C p.Ala737Pro missense_variant Familial - Extended multiplex (at least one pair of ASD affec 24410847 Cukier HN , et al. (2014)
Common Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.-68-4A>G;c.242-4A>G - intron_variant - - - 23915500 Chien WH , et al. (2013)
c.1151C>A;c.1460C>A p.Pro384Gln missense_variant - - - 23915500 Chien WH , et al. (2013)
SFARI Gene score
3

Suggestive Evidence

In ASD-associated CNVs (Pinto et al., 2010) for which at present there is not independent evidence.

Score Delta: Score remained at 4

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

4/1/2020
4
icon
4

Score remained at 4

Description

In ASD-associated CNVs (Pinto et al., 2010) for which at present there is not independent evidence.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

In ASD-associated CNVs (Pinto et al., 2010) for which at present there is not independent evidence.

Reports Added
[New Scoring Scheme]
7/1/2016
4
icon
4

Decreased from 4 to 4

Description

In ASD-associated CNVs (Pinto et al., 2010) for which at present there is not independent evidence.

7/1/2014
No data
icon
4

Increased from No data to 4

Description

In ASD-associated CNVs (Pinto et al., 2010) for which at present there is not independent evidence.

4/1/2014
No data
icon
4

Increased from No data to 4

Description

In ASD-associated CNVs (Pinto et al., 2010) for which at present there is not independent evidence.

Krishnan Probability Score

Score 0.62762954543632

Ranking 72/25841 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 0.95039732591759

Ranking 2674/18225 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 0.929

Ranking 111/239 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 0.74983049102443

Ranking 1553/18665 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 29

Ranking 73/461 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 0.42599030081975

Ranking 1166/20870 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
KRTAP4-2 keratin associated protein 4-2 Human Protein Binding 85291 Q9BYR5
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