Human Gene Module / Chromosome 17 / DLG4

DLG4discs large MAGUK scaffold protein 4

Hypothesized Criteria 5.1
Autism Reports / Total Reports
3 / 10
Rare Variants / Common Variants
13 / 0
DLG4, PSD95,  SAP-90,  SAP90
Associated Syndromes
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Chromosome Band
Associated Disorders
Relevance to Autism

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.

Reports related to DLG4 (10 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' ... 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 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 -
7 Recent Recommendation Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Lelieveld SH , et al. (2016) No -
8 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Stessman HA , et al. (2017) No -
9 Support Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features. Sbastien M , et al. (2018) No ASD
10 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes. Guo H , et al. (2018) Yes -
Rare Variants   (13)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.20-1G>C p? splice_site_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.1124A>G p.Asp375Gly missense_variant Unknown - - 27271353 Xing J , et al. (2016)
c.1054C>T p.Arg352Ter stop_gained De novo - - 27479843 Lelieveld SH , et al. (2016)
c.1231C>T p.Arg411Ter stop_gained De novo - - 27479843 Lelieveld SH , et al. (2016)
c.2281G>A p.Val761Ile missense_variant Unknown - Unknown 25549968 Li J , et al. (2015)
c.277dup p.Tyr93fs frameshift_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
c.583G>A p.Gly241Ser missense_variant Familial - Simplex 27271353 Xing J , et al. (2016)
c.1961C>T p.Thr654Ile missense_variant De novo - Simplex 23020937 Rauch A , et al. (2012)
c.20-1G>C p.? splice_site_variant Familial Maternal Simplex 30504930 Guo H , et al. (2018)
c.1843delG p.Glu615SerfsTer4 frameshift_variant De novo - - 29460436 Sbastien M , et al. (2018)
c.1147_1154delTTTATCCT p.Phe383GlyfsTer31 frameshift_variant De novo - - 29460436 Sbastien M , et al. (2018)
c.347C>G p.Ser116Ter stop_gained De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.1672+2T>C p.Gly558ProfsTer37 splice_site_variant Unknown Not maternal - 29460436 Sbastien M , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score





See all Category 5 Genes

Category 5.1 includes genes for which the only evidence comes from studies of model organisms, without statistical or genetic support in human studies.

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: A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at
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 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: aned_exac_nonTCGA_z_pli_rec_null_data.txt
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
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.
CNVs associated with DLG4(1 CNVs)
17p13.1 26 Deletion-Duplication 40  /  153
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
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