Human Gene Module / Chromosome 11 / DLG2

DLG2discs large MAGUK scaffold protein 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 15
Rare Variants / Common Variants
16 / 0
Aliases
DLG2, PPP1R58,  PSD-93,  PSD93,  chapsyn-110
Associated Syndromes
-
Chromosome Band
11q14.1
Associated Disorders
-
Relevance to Autism

A de novo missense variant that was predicted by PolyPhen-2 to be probably damaging (Mis3) was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). Ruzzo et al., 2019 identified three multiplex ASD families from the iHART cohort in which at least one proband in each family had a 2.5-kb deletion in the promoter of the DLG2 gene; no deletions were found to overlap the DLG2 promoter in 26,565 controls, and this deletion was determined to be significantly associated with ASD (3 of 484 unrelated affected children vs. 0 of 2,889 WGS controls, two-sided Fishers exact test, p = 0.003, OR = Inf, 95% CI = 2.47-Inf).

Molecular Function

This gene encodes a member of the membrane-associated guanylate kinase (MAGUK) family. The encoded protein forms a heterodimer with a related family member that 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
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to DLG2 (15 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Recent Recommendation Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
3 Support - Sanders B et al. (2022) No -
4 Support - Waldron S et al. (2022) No -
5 Support - Griesius S et al. (2022) No -
6 Support - Pass R et al. (2022) No -
7 Support - Bertini V et al. (2022) No ASD or autistic features, ADHD, ODD, epilepsy/seiz
8 Support - Kushima I et al. (2022) No -
9 Support - Krgovic D et al. (2022) Yes ADHD, DD, ID
10 Support - Yoo T et al. (2022) No -
11 Support - Zhou X et al. (2022) Yes -
12 Support - Cirnigliaro M et al. (2023) Yes -
13 Support - Simonas Griesius et al. (2023) No -
14 Support - Yunjia Chen et al. (2024) No ASD, ADHD, epilepsy/seizures
15 Support - Mehdi Agha Gholizadeh et al. () Yes DD, ID
Rare Variants   (16)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Unknown - - 35627244 Bertini V et al. (2022)
- - copy_number_loss Unknown - - 37860969 Yunjia Chen et al. (2024)
- - copy_number_gain Familial Maternal - 35627244 Bertini V et al. (2022)
- - copy_number_loss Familial Maternal - 35627244 Bertini V et al. (2022)
- - copy_number_loss Familial Paternal - 35627244 Bertini V et al. (2022)
- - copy_number_loss Unknown - Multiplex 31398340 Ruzzo EK , et al. (2019)
- - copy_number_loss Unknown - Simplex 37860969 Yunjia Chen et al. (2024)
- - copy_number_loss Unknown - Unknown 37860969 Yunjia Chen et al. (2024)
- - copy_number_loss Unknown - Multiplex 37860969 Yunjia Chen et al. (2024)
c.1478C>G p.Pro493Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.285A>G p.Gln95%3D splice_region_variant De novo - - 35813072 Krgovic D et al. (2022)
c.1793C>G p.Thr598Arg missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
- - intron_variant Familial Both parents Multiplex 38976082 Mehdi Agha Gholizadeh et al. ()
c.1497-2A>G - splice_site_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.2194-3_2194-2del - splice_site_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo missense variant that was predicted by PolyPhen-2 to be probably damaging (Mis3) was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). Ruzzo et al., 2019 identified three multiplex ASD families from the iHART cohort in which at least one proband in each family had a 2.5-kb deletion in the promoter of the DLG2 gene; no deletions were found to overlap the DLG2 promoter in 26,565 controls, and this deletion was determined to be significantly associated with ASD (3 of 484 unrelated affected children vs. 0 of 2,889 WGS controls, two-sided Fishers exact test, p = 0.003, OR = Inf, 95% CI = 2.47-Inf).

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.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

A de novo missense variant that was predicted by PolyPhen-2 to be probably damaging (Mis3) was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). Ruzzo et al., 2019 identified three multiplex ASD families from the iHART cohort in which at least one proband in each family had a 2.5-kb deletion in the promoter of the DLG2 gene; no deletions were found to overlap the DLG2 promoter in 26,565 controls, and this deletion was determined to be significantly associated with ASD (3 of 484 unrelated affected children vs. 0 of 2,889 WGS controls, two-sided Fishers exact test, p = 0.003, OR = Inf, 95% CI = 2.47-Inf).

Reports Added
[New Scoring Scheme]
7/1/2019
icon
3

Increased from to 3

Description

A de novo missense variant that was predicted by PolyPhen-2 to be probably damaging (Mis3) was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). Ruzzo et al., 2019 identified three multiplex ASD families from the iHART cohort in which at least one proband in each family had a 2.5-kb deletion in the promoter of the DLG2 gene; no deletions were found to overlap the DLG2 promoter in 26,565 controls, and this deletion was determined to be significantly associated with ASD (3 of 484 unrelated affected children vs. 0 of 2,889 WGS controls, two-sided Fishers exact test, p = 0.003, OR = Inf, 95% CI = 2.47-Inf).

Krishnan Probability Score

Score 0.60836860679474

Ranking 284/25841 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 0.67354537016186

Ranking 4622/18225 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 0.95058750622931

Ranking 18551/18665 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 0.41015585491736

Ranking 1345/20870 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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