Human Gene Module / Chromosome 17 / DLG4

DLG4discs large MAGUK scaffold protein 4

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
11 / 25
Rare Variants / Common Variants
80 / 0
EAGLE Score
2.45
Limited Learn More
Aliases
DLG4, PSD95,  SAP-90,  SAP90
Associated Syndromes
-
Chromosome Band
17p13.1
Associated Disorders
DD/NDD, ADHD, ID, EPS, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Relevance to Autism

Four de novo likely gene-disruptive (LGD) variants in the DLG4 gene were identified in ASD probands (three from the SPARK cohort, one from the ITAN cohort) in Wang et al., 2020. DLG4 knockout mice displayed increased repetitive behaviors, abnormal communication and social behaviors, impaired motor coordination, and increased stress reactivity and anxiety-related responses (Feyder et al., 2010). In the same report, significant association was observed between variations in two human DLG4 SNPs and reduced intraparietal sulcus volume and abnormal cortico-amygdala coupling in a normal population. DLG4 was identified in Stessman et al., 2017 as a gene reaching de novo significance for loss-of-function variants in NDD cases (FDR-corrected de novo P-value of 3.77E-03).

Molecular Function

This gene encodes a member of the membrane-associated guanylate kinase (MAGUK) family. It heteromultimerizes with another MAGUK protein, DLG2, and is recruited into NMDA receptor and potassium channel clusters. These two MAGUK proteins may interact at postsynaptic sites to form a multimeric scaffold for the clustering of receptors, ion channels, and associated signaling proteins.

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 DLG4 (25 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Association of mouse Dlg4 (PSD-95) gene deletion and human DLG4 gene variation with phenotypes relevant to autism spectrum disorders and Williams' syndrome Feyder M , et al. (2010) No -
2 Support Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study Rauch A , et al. (2012) No Epilepsy, ASD
3 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
4 Recent Recommendation Integrated systems analysis reveals a molecular network underlying autism spectrum disorders Li J , et al. (2015) Yes -
5 Recent Recommendation Synaptic Consolidation Normalizes AMPAR Quantal Size following MAGUK Loss Levy JM , et al. (2015) No -
6 Support - Bosch DG et al. (2016) No ASD, DD, ID
7 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 -
8 Recent Recommendation Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
9 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases Stessman HA , et al. (2017) No -
10 Support Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features Sbastien M , et al. (2018) No ASD
11 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes Guo H , et al. (2018) Yes -
12 Support - Baker SW et al. (2019) No -
13 Support Autism-associated missense genetic variants impact locomotion and neurodevelopment in Caenorhabditis elegans Wong WR , et al. (2019) Yes -
14 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
15 Recent recommendation - Rodríguez-Palmero A et al. (2021) No ASD, ADHD, epilepsy/seizures
16 Support - Pode-Shakked B et al. (2021) No -
17 Support - Brea-Fernández AJ et al. (2022) Yes -
18 Support - Zhou X et al. (2022) Yes -
19 Support - Spataro N et al. (2023) No -
20 Support - Wang J et al. (2023) Yes -
21 Support - Balasar et al. (2023) No Autistic features
22 Support - Levy AM et al. (2023) Yes -
23 Support - Sheth F et al. (2023) Yes DD, ID
24 Support - Sachi Tokunaga et al. (2024) Yes Developmental regression
25 Support - Tamam Khalaf 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.921T>A p.Tyr307Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
- - frameshift_variant De novo - Simplex 29460436 Sbastien M , et al. (2018)
c.1231C>T p.Arg411Ter stop_gained De novo - - 33004838 Wang T et al. (2020)
c.1615C>T p.Arg539Ter stop_gained De novo - - 33004838 Wang T et al. (2020)
c.1801A>T p.Lys601Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.*165C>T - intron_variant Unknown - Simplex 37525972 Levy AM et al. (2023)
c.1582+7C>T - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
n.2988+2T>A p.? splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.1054C>T p.Arg352Ter stop_gained De novo - - 36980980 Spataro N et al. (2023)
c.20-1G>C - splice_site_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.590C>T p.Pro197Leu missense_variant De novo - - 33004838 Wang T et al. (2020)
c.1283C>T p.Thr428Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1550G>A p.Arg517Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1798G>A p.Asp600Asn missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1843G>A p.Glu615Lys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2081G>A p.Arg694His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2203G>A p.Val735Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2203G>T p.Val735Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3G>A p.Met1? initiator_codon_variant Unknown - - 33004838 Wang T et al. (2020)
c.1124A>G p.Asp375Gly missense_variant Unknown - - 27271353 Xing J , et al. (2016)
c.1625G>A p.Trp542Ter stop_gained De novo - Simplex 30577886 Baker SW et al. (2019)
c.2281G>A p.Val761Ile missense_variant Unknown - Unknown 25549968 Li J , et al. (2015)
c.1534+2T>C - splice_site_variant De novo - Simplex 29460436 Sbastien M , et al. (2018)
c.452dup p.Ala152GlyfsTer2 frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.1973C>T p.Ser658Phe missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1054C>T p.Arg352Ter stop_gained De novo - Simplex 27479843 Lelieveld SH et al. (2016)
c.1231C>T p.Arg411Ter stop_gained De novo - Simplex 27479843 Lelieveld SH et al. (2016)
c.2271del p.Tyr758ThrfsTer32 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1961C>T p.Thr654Ile missense_variant De novo - Simplex 23020937 Rauch A , et al. (2012)
c.201+1G>T - splice_site_variant Unknown - - 33597769 Rodríguez-Palmero A et al. (2021)
c.2290C>T p.Arg764Ter stop_gained Familial Paternal Simplex 33004838 Wang T et al. (2020)
c.1618C>T p.Arg540Ter stop_gained Unknown - - 33597769 Rodríguez-Palmero A et al. (2021)
c.1675C>T p.Arg559Ter stop_gained Unknown - - 33597769 Rodríguez-Palmero A et al. (2021)
c.8del p.Cys3PhefsTer4 frameshift_variant Unknown - Simplex 37524782 Balasar et al. (2023)
c.1129G>A p.Glu377Lys missense_variant De novo - - 35322241 Brea-Fernández AJ et al. (2022)
c.907del p.Asp303ThrfsTer10 frameshift_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.19G>C p.Val7Leu splice_site_variant Familial Maternal Simplex 30504930 Guo H , et al. (2018)
c.1039del p.Ala347GlnfsTer33 frameshift_variant Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.583G>A p.Gly241Ser missense_variant Familial Maternal Simplex 27271353 Xing J , et al. (2016)
c.515C>T p.Thr172Ile missense_variant Familial Maternal Simplex 37543562 Sheth F et al. (2023)
c.778+2T>C - splice_site_variant De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.1083G>A p.Ser361%3D synonymous_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.322G>T p.Glu108Ter stop_gained De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.448C>T p.Gln150Ter stop_gained De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.607G>T p.Glu203Ter stop_gained De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.921T>A p.Tyr307Ter stop_gained De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.1469+2T>C - splice_site_variant De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.1684+1G>A - splice_site_variant De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.1721-1G>A - splice_site_variant De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.1054C>T p.Arg352Ter stop_gained De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.1186C>T p.Arg396Ter stop_gained De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.1324C>T p.Arg442Ter stop_gained De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.1330G>T p.Glu444Ter stop_gained De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.1618C>T p.Arg540Ter stop_gained De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.1626G>A p.Trp542Ter stop_gained De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.1801A>T p.Lys601Ter stop_gained De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.1978C>T p.Arg660Ter stop_gained De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.2007C>A p.Cys669Ter stop_gained De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.504del p.Phe169SerfsTer7 frameshift_variant De novo - Simplex 29460436 Sbastien M , et al. (2018)
c.554_563del p.Gly185AlafsTer4 frameshift_variant De novo - - 38182567 Sachi Tokunaga et al. (2024)
c.1213-1G>T - splice_site_variant Familial Maternal - 33597769 Rodríguez-Palmero A et al. (2021)
c.277dup p.Tyr93LeufsTer20 frameshift_variant De novo - Simplex 27479843 Lelieveld SH et al. (2016)
c.659G>T p.Gly220Val missense_variant De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.686A>T p.Asp229Val missense_variant De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.1054C>T p.Arg352Ter stop_gained Unknown Not maternal - 33597769 Rodríguez-Palmero A et al. (2021)
c.1886G>A p.Arg629Gln missense_variant De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.1425dup p.Asp476Ter frameshift_variant De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.1119C>T p.Gly373%3D synonymous_variant De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.1212G>A p.Ser404%3D synonymous_variant De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.1469+4_1469+19del - splice_region_variant De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.347C>G p.Ser116Ter stop_gained De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.234dup p.Gly79TrpfsTer3 frameshift_variant De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.330del p.Asn111ThrfsTer7 frameshift_variant De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.317del p.Gly106AlafsTer12 frameshift_variant De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.516dup p.Gly173ArgfsTer12 frameshift_variant De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.596del p.Lys199ArgfsTer19 frameshift_variant De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.1846del p.Val616TrpfsTer41 frameshift_variant De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
c.1449del p.Phe484SerfsTer16 frameshift_variant Unknown - Multiplex 33597769 Rodríguez-Palmero A et al. (2021)
c.340-2A>G - splice_site_variant De novo - Multiplex (monozygotic twins) 33597769 Rodríguez-Palmero A et al. (2021)
c.2203_2207delinsT p.Val735TrpfsTer12 frameshift_variant De novo - Simplex 33597769 Rodríguez-Palmero A et al. (2021)
Common Variants  

No common variants reported.

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.

1/1/2021
1
icon
1

Score remained at 1

Description

DLG4 knockout mice displayed increased repetitive behaviors, abnormal communication and social behaviors, impaired motor coordination, and increased stress reactivity and anxiety-related responses (Feyder et al., 2010). In the same report, significant association was observed between variations in two human DLG4 SNPs and reduced intraparietal sulcus volume and abnormal cortico-amygdala coupling in a normal population. DLG4 was identified in Stessman et al., 2017 as a gene reaching de novo significance for loss-of-function variants in NDD cases (FDR-corrected de novo P-value of 3.77E-03).

Reports Added
[Novel genetic causes for cerebral visual impairment2016] [Automated Clinical Exome Reanalysis Reveals Novel Diagnoses2019] [DLG4-related synaptopathy: a new rare brain disorder2021]
10/1/2020
1
icon
1

Score remained at 1

Description

DLG4 knockout mice displayed increased repetitive behaviors, abnormal communication and social behaviors, impaired motor coordination, and increased stress reactivity and anxiety-related responses (Feyder et al., 2010). In the same report, significant association was observed between variations in two human DLG4 SNPs and reduced intraparietal sulcus volume and abnormal cortico-amygdala coupling in a normal population. DLG4 was identified in Stessman et al., 2017 as a gene reaching de novo significance for loss-of-function variants in NDD cases (FDR-corrected de novo P-value of 3.77E-03).

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
10/1/2019
5
icon
1

Decreased from 5 to 1

New Scoring Scheme
Description

DLG4 knockout mice displayed increased repetitive behaviors, abnormal communication and social behaviors, impaired motor coordination, and increased stress reactivity and anxiety-related responses (Feyder et al., 2010). In the same report, significant association was observed between variations in two human DLG4 SNPs and reduced intraparietal sulcus volume and abnormal cortico-amygdala coupling in a normal population. DLG4 was identified in Stessman et al., 2017 as a gene reaching de novo significance for loss-of-function variants in NDD cases (FDR-corrected de novo P-value of 3.77E-03).

Reports Added
[New Scoring Scheme]
7/1/2019
5
icon
5

Decreased from 5 to 5

Description

DLG4 knockout mice displayed increased repetitive behaviors, abnormal communication and social behaviors, impaired motor coordination, and increased stress reactivity and anxiety-related responses (Feyder et al., 2010). In the same report, significant association was observed between variations in two human DLG4 SNPs and reduced intraparietal sulcus volume and abnormal cortico-amygdala coupling in a normal population. DLG4 was identified in Stessman et al., 2017 as a gene reaching de novo significance for loss-of-function variants in NDD cases (FDR-corrected de novo P-value of 3.77E-03).

Reports Added
[Autism-associated missense genetic variants impact locomotion and neurodevelopment in Caenorhabditis elegans.2019]
10/1/2018
5
icon
5

Decreased from 5 to 5

Description

DLG4 knockout mice displayed increased repetitive behaviors, abnormal communication and social behaviors, impaired motor coordination, and increased stress reactivity and anxiety-related responses (Feyder et al., 2010). In the same report, significant association was observed between variations in two human DLG4 SNPs and reduced intraparietal sulcus volume and abnormal cortico-amygdala coupling in a normal population. DLG4 was identified in Stessman et al., 2017 as a gene reaching de novo significance for loss-of-function variants in NDD cases (FDR-corrected de novo P-value of 3.77E-03).

Reports Added
[Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.2018]
7/1/2018
icon
5

Increased from to 5

Description

DLG4 knockout mice displayed increased repetitive behaviors, abnormal communication and social behaviors, impaired motor coordination, and increased stress reactivity and anxiety-related responses (Feyder et al., 2010). In the same report, significant association was observed between variations in two human DLG4 SNPs and reduced intraparietal sulcus volume and abnormal cortico-amygdala coupling in a normal population. DLG4 was identified in Stessman et al., 2017 as a gene reaching de novo significance for loss-of-function variants in NDD cases (FDR-corrected de novo P-value of 3.77E-03).

Krishnan Probability Score

Score 0.57242134998071

Ranking 707/25841 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 0.99659266640088

Ranking 1402/18225 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 0.92306238704364

Ranking 9700/18665 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 0.11128250919073

Ranking 5895/20870 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
CC2D1A coiled-coil and C2 domain containing 1A Human Protein Binding 54862 Q6P1N0
ERBB4 v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian) Human Protein Binding 2066 Q15303
IGSF11 immunoglobulin superfamily member 11 Human Protein Binding 152404 Q5DX21
IL1RAPL1 interleukin 1 receptor accessory protein-like 1 Human Protein Binding 11141 Q9NZN1
Lrrtm3 leucine rich repeat transmembrane neuronal 3 Mouse Protein Binding 216028 Q8BZ81
Lrrtm4 leucine rich repeat transmembrane neuronal 4 Mouse Protein Binding 243499 Q80XG9
NLGN3 neuroligin 3 Rat Protein Binding 171297 Q62889
NLGN4X neuroligin 4, X-linked Human Protein Binding 57502 Q8N0W4
Rph3a rabphilin 3A homolog (mouse) Rat Protein Binding 22895 P47709
SHANK2 SH3 and multiple ankyrin repeat domains 2 Rat Protein Binding 171093 Q9QX74
Shisa6 shisa family member 6 Mouse Protein Binding 380702 Q3UH99
SYNGAP1 synaptic Ras GTPase activating protein 1 Human Protein Binding 8831 Q96PV0
Submit New Gene

Report an Error