Human Gene Module / Chromosome 18 / DLGAP1

DLGAP1DLG associated protein 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
9 / 13
Rare Variants / Common Variants
18 / 0
Aliases
DLGAP1, DAP-1,  DAP-1-ALPHA,  DAP-1-BETA,  DAP1A,  DLGAP1B,  GKAP,  SAPAP1,  hGKAP,  DLGAP1
Associated Syndromes
-
Chromosome Band
18p11.31
Associated Disorders
-
Relevance to Autism

This gene was originally identified as an ASD candidate gene based on its enrichment in an autism-associated protein interaction module; sequencing of post-mortem brain tissue from 25 ASD cases resulted in the identification of significant non-synonymous variants in this gene with an expected false-positive rate at 0.1, confirming the involvement of this module with autism (Li et al., 2014).

Molecular Function

The protein encoded by this gene is expressed in the brain, localizes to the postsynaptic density, and interacts with a number of ASD-associated proteins, including DLG1, DLG4, SHANK1, SHANK2 and SHANK3.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to DLGAP1 (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
2 Primary Integrated systems analysis reveals a molecular network underlying autism spectrum disorders Li J , et al. (2015) Yes -
3 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 -
4 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
5 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases Stessman HA , et al. (2017) Yes -
6 Support Dlgap1 knockout mice exhibit alterations of the postsynaptic density and selective reductions in sociability Coba MP , et al. (2018) No -
7 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
8 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
9 Support De Novo Damaging DNA Coding Mutations Are Associated With Obsessive-Compulsive Disorder and Overlap With Tourette's Disorder and Autism Cappi C , et al. (2019) No -
10 Support - Alonso-Gonzalez A et al. (2021) Yes -
11 Support - Mitani T et al. (2021) No -
12 Support - Zhou X et al. (2022) Yes -
13 Support - Sheth F et al. (2023) Yes DD, ID
Rare Variants   (18)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.22C>A p.Arg8Ser missense_variant Unknown - - 27271353 Xing J , et al. (2016)
c.215G>A p.Arg72His missense_variant Unknown - - 27271353 Xing J , et al. (2016)
c.2276C>A p.Thr759Lys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.497G>A p.Gly166Asp missense_variant Unknown - - 27271353 Xing J , et al. (2016)
c.1175T>C p.Ile392Thr missense_variant Unknown - - 27271353 Xing J , et al. (2016)
c.1273G>A p.Asp703Asn missense_variant Unknown - - 27271353 Xing J , et al. (2016)
c.2260G>A p.Asp754Asn missense_variant Unknown - - 27271353 Xing J , et al. (2016)
c.230C>T p.Ser77Leu missense_variant Unknown - Unknown 25549968 Li J , et al. (2015)
c.612G>A p.Ser204= synonymous_variant De novo - - 31452935 Feliciano P et al. (2019)
c.215G>A p.Arg72His missense_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.575A>G p.Lys192Arg missense_variant De novo - Simplex 31771860 Cappi C , et al. (2019)
c.424G>T p.Val142Leu missense_variant Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.1818+2T>C - splice_site_variant De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.293G>A p.Arg98His missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.1082C>T p.Thr361Met missense_variant Familial Paternal Simplex 37543562 Sheth F et al. (2023)
c.215G>A p.Arg72His missense_variant Familial Both parents Multiplex 34582790 Mitani T et al. (2021)
c.122G>A p.Arg41Gln missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.1002G>A p.Thr334= synonymous_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

This gene was originally identified as an ASD candidate gene based on its enrichment in an autism-associated protein interaction module; sequencing of post-mortem brain tissue from 25 ASD cases resulted in the identification of significant non-synonymous variants in this gene with an expected false-positive rate at 0.1, confirming the involvement of this module with autism (Li et al., 2014). A number of missense variants in DLGAP1 were observed in individuals from a cohort of 370 schizophrenia cases and 192 ASD cases in Xing et al., 2016. Damaging missense variants (CADD scores > 30), one of which was de novo in origin, were identified in ASD probands in two reports (Wang et al., 2016; Stessman et al., 2017). The protein encoded by this gene is expressed in the brain, localizes to the postsynaptic density, and interacts with a number of ASD-associated proteins, including DLG1, DLG4, SHANK1, SHANK2 and SHANK3. DLGAP1-knockout mice were recently shown to exhibit alterations of the postsynaptic density and selective reductions in sociability (Coba et al., 2018).

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.

1/1/2021
2
icon
2

Score remained at 2

Description

This gene was originally identified as an ASD candidate gene based on its enrichment in an autism-associated protein interaction module; sequencing of post-mortem brain tissue from 25 ASD cases resulted in the identification of significant non-synonymous variants in this gene with an expected false-positive rate at 0.1, confirming the involvement of this module with autism (Li et al., 2014). A number of missense variants in DLGAP1 were observed in individuals from a cohort of 370 schizophrenia cases and 192 ASD cases in Xing et al., 2016. Damaging missense variants (CADD scores > 30), one of which was de novo in origin, were identified in ASD probands in two reports (Wang et al., 2016; Stessman et al., 2017). The protein encoded by this gene is expressed in the brain, localizes to the postsynaptic density, and interacts with a number of ASD-associated proteins, including DLG1, DLG4, SHANK1, SHANK2 and SHANK3. DLGAP1-knockout mice were recently shown to exhibit alterations of the postsynaptic density and selective reductions in sociability (Coba et al., 2018).

Reports Added
[Exploring the biological role of postzygotic and germinal de novo mutations in ASD2021]
1/1/2020
2
icon
2

Score remained at 2

Description

This gene was originally identified as an ASD candidate gene based on its enrichment in an autism-associated protein interaction module; sequencing of post-mortem brain tissue from 25 ASD cases resulted in the identification of significant non-synonymous variants in this gene with an expected false-positive rate at 0.1, confirming the involvement of this module with autism (Li et al., 2014). A number of missense variants in DLGAP1 were observed in individuals from a cohort of 370 schizophrenia cases and 192 ASD cases in Xing et al., 2016. Damaging missense variants (CADD scores > 30), one of which was de novo in origin, were identified in ASD probands in two reports (Wang et al., 2016; Stessman et al., 2017). The protein encoded by this gene is expressed in the brain, localizes to the postsynaptic density, and interacts with a number of ASD-associated proteins, including DLG1, DLG4, SHANK1, SHANK2 and SHANK3. DLGAP1-knockout mice were recently shown to exhibit alterations of the postsynaptic density and selective reductions in sociability (Coba et al., 2018).

Reports Added
[De Novo Damaging DNA Coding Mutations Are Associated With Obsessive-Compulsive Disorder and Overlap With Tourette's Disorder and Autism.2019]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

This gene was originally identified as an ASD candidate gene based on its enrichment in an autism-associated protein interaction module; sequencing of post-mortem brain tissue from 25 ASD cases resulted in the identification of significant non-synonymous variants in this gene with an expected false-positive rate at 0.1, confirming the involvement of this module with autism (Li et al., 2014). A number of missense variants in DLGAP1 were observed in individuals from a cohort of 370 schizophrenia cases and 192 ASD cases in Xing et al., 2016. Damaging missense variants (CADD scores > 30), one of which was de novo in origin, were identified in ASD probands in two reports (Wang et al., 2016; Stessman et al., 2017). The protein encoded by this gene is expressed in the brain, localizes to the postsynaptic density, and interacts with a number of ASD-associated proteins, including DLG1, DLG4, SHANK1, SHANK2 and SHANK3. DLGAP1-knockout mice were recently shown to exhibit alterations of the postsynaptic density and selective reductions in sociability (Coba et al., 2018).

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
1/1/2019
3
icon
3

Decreased from 3 to 3

Description

This gene was originally identified as an ASD candidate gene based on its enrichment in an autism-associated protein interaction module; sequencing of post-mortem brain tissue from 25 ASD cases resulted in the identification of significant non-synonymous variants in this gene with an expected false-positive rate at 0.1, confirming the involvement of this module with autism (Li et al., 2014). A number of missense variants in DLGAP1 were observed in individuals from a cohort of 370 schizophrenia cases and 192 ASD cases in Xing et al., 2016. Damaging missense variants (CADD scores > 30), one of which was de novo in origin, were identified in ASD probands in two reports (Wang et al., 2016; Stessman et al., 2017). The protein encoded by this gene is expressed in the brain, localizes to the postsynaptic density, and interacts with a number of ASD-associated proteins, including DLG1, DLG4, SHANK1, SHANK2 and SHANK3. DLGAP1-knockout mice were recently shown to exhibit alterations of the postsynaptic density and selective reductions in sociability (Coba et al., 2018).

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
7/1/2018
icon
3

Increased from to 3

Description

This gene was originally identified as an ASD candidate gene based on its enrichment in an autism-associated protein interaction module; sequencing of post-mortem brain tissue from 25 ASD cases resulted in the identification of significant non-synonymous variants in this gene with an expected false-positive rate at 0.1, confirming the involvement of this module with autism (Li et al., 2014). A number of missense variants in DLGAP1 were observed in individuals from a cohort of 370 schizophrenia cases and 192 ASD cases in Xing et al., 2016. Damaging missense variants (CADD scores > 30), one of which was de novo in origin, were identified in ASD probands in two reports (Wang et al., 2016; Stessman et al., 2017). The protein encoded by this gene is expressed in the brain, localizes to the postsynaptic density, and interacts with a number of ASD-associated proteins, including DLG1, DLG4, SHANK1, SHANK2 and SHANK3. DLGAP1-knockout mice were recently shown to exhibit alterations of the postsynaptic density and selective reductions in sociability (Coba et al., 2018).

Krishnan Probability Score

Score 0.60353762061072

Ranking 363/25841 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 0.99304551428356

Ranking 1659/18225 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 0.95004101463091

Ranking 18334/18665 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 0.59611276742204

Ranking 91/20870 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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