DLG4

Chr 17AD

discs large MAGUK scaffold protein 4

ENSG00000132535 UniProt: P78352 OMIM: 602887

The DLG4 protein heteromultimerizes with DLG2 to form postsynaptic scaffolds that cluster NMDA receptors, potassium channels, and associated signaling proteins at synapses. Loss-of-function mutations cause autosomal dominant intellectual developmental disorder. The high constraint scores (pLI 0.999, LOEUF 0.238) indicate this gene is highly intolerant to loss-of-function variants, consistent with the dominant inheritance pattern where haploinsufficiency disrupts synaptic function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Postsynaptic scaffolding protein that plays a critical role in synaptogenesis and synaptic plasticity by providing a platform for the postsynaptic clustering of crucial synaptic proteins. Interacts with the cytoplasmic tail of NMDA receptor subunits and shaker-type potassium channels. Required for synaptic plasticity associated with NMDA receptor signaling. Overexpression or depletion of DLG4 changes the ratio of excitatory to inhibitory synapses in hippocampal neurons. May reduce the amplitude of ASIC3 acid-evoked currents by retaining the channel intracellularly. May regulate the intracellular trafficking of ADR1B. Also regulates AMPA-type glutamate receptor (AMPAR) immobilization at postsynaptic density keeping the channels in an activated state in the presence of glutamate and preventing synaptic depression (By similarity). Under basal conditions, cooperates with FYN to stabilize palmitoyltransferase ZDHHC5 at the synaptic membrane through FYN-mediated phosphorylation of ZDHHC5 and its subsequent inhibition of association with endocytic proteins (PubMed:26334723)

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.241 OMIM phenotype

Clinical Summary— DLG4

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

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Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.24LOEUF

pLI 1.000

Z-score 5.46

OE 0.11 (0.06–0.24)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

4.93Z-score

OE missense 0.36 (0.32–0.41)

174 obs / 477.3 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.11 (0.06–0.24)

0≤0.351.4

Missense OE?0.36 (0.32–0.41)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 5 / 44.1Missense obs/exp: 174 / 477.3Syn Z: 0.82

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongDLG4-related intellectual disabilityLOFAD

This gene — mechanism propensity

0.4685th %ile

GOF

0.6248th %ile

LOF

0.71top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · LOEUF 0.24 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFIn a 23-year-old French man (patient 1) with autosomal dominant intellectual developmental disorder-62 (MRD62; 618793), Moutton et al. (2018) identified a de novo heterozygous 1-bp deletion (c.1843delG, NM_001365.3) in exon 19 of the DLG4 gene, resulting in a frameshift and premature termination (Gl1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References