Human Gene Module / Chromosome 3 / DLG1

DLG1discs large MAGUK scaffold protein 1

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
4 / 4
Rare Variants / Common Variants
9 / 0
Aliases
DLG1, DLGH1,  SAP-97,  SAP97,  dJ1061C18.1.1,  hdlg
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
3q29
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; this finding was further validated by exome sequencing of an independent cohort of 505 ASD cases and 491 controls (Li et al., 2014).

Molecular Function

This gene encodes a multi-domain scaffolding protein that is required for normal development. This protein may have a role in septate junction formation, signal transduction, cell proliferation, synaptogenesis and lymphocyte activation.

Reports related to DLG1 (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Integrated systems analysis reveals a molecular network underlying autism spectrum disorders. Li J , et al. (2015) Yes -
2 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 -
3 Support Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder. Krupp DR , et al. (2017) Yes -
4 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
Rare Variants   (9)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.215C>T p.Pro72Leu missense_variant Familial - - 27271353 Xing J , et al. (2016)
c.1030G>C p.Gly344Arg missense_variant Unknown - - 27271353 Xing J , et al. (2016)
c.1143A>C p.Glu381Asp missense_variant Unknown - - 27271353 Xing J , et al. (2016)
c.1470C>G p.Asn606Lys missense_variant Unknown - - 27271353 Xing J , et al. (2016)
c.1552G>C p.Val518Leu missense_variant Unknown - - 27271353 Xing J , et al. (2016)
c.2186A>T p.Asn729Ile missense_variant Unknown - - 27271353 Xing J , et al. (2016)
c.85C>T p.Gln29Ter stop_gained De novo NA Simplex 28867142 Krupp DR , et al. (2017)
c.1998T>G p.Asp666Glu missense_variant Unknown - Unknown 25549968 Li J , et al. (2015)
c.1249C>T p.Pro417Ser missense_variant De novo NA - 31452935 Feliciano P et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

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; this finding was further validated by exome sequencing of an independent cohort of 505 ASD cases and 491 controls (Li et al., 2014). Missense variants in the DLG1 gene have been identified in a cohort consisting of patients with ASD or schizophrenia (Xing et al., 2016). A de novo nonsense variant in DLG1 was identified as a mosaic mutation with an allele frequency of 4% in an ASD proband from the Simons Simplex Collection in Krupp et al., 2017.

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.

10/1/2019
4
icon
3

Decreased from 4 to 3

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; this finding was further validated by exome sequencing of an independent cohort of 505 ASD cases and 491 controls (Li et al., 2014). Missense variants in the DLG1 gene have been identified in a cohort consisting of patients with ASD or schizophrenia (Xing et al., 2016). A de novo nonsense variant in DLG1 was identified as a mosaic mutation with an allele frequency of 4% in an ASD proband from the Simons Simplex Collection in Krupp et al., 2017.

4/1/2018
icon
4.4

Increased from to 4.4

Description

4

Krishnan Probability Score

Score 0.45203457116235

Ranking 10557/25841 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 0.9987420492048

Ranking 1127/18225 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
Sanders TADA Score

Score 0.94105843042573

Ranking 14793/18665 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).
Zhang D Score

Score 0.4783379658757

Ranking 674/20870 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.
CNVs associated with DLG1(1 CNVs)
3q29 56 Deletion-Duplication 89  /  437
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
ADGRA2 adhesion G protein-coupled receptor A2 Human Protein Binding 25960 Q96PE1
GJB7 Gap junction beta-7 protein Human Protein Binding 375519 Q6PEY0
GPRC5B G-protein coupled receptor family C group 5 member B Human Protein Binding 51704 Q9NZH0
PARK2 Parkinson disease (autosomal recessive, juvenile) 2, parkin Mouse Protein Binding 50873 Q9WVS6
PRDM1 PR domain zinc finger protein 1 Human Protein Binding 639 O75626
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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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