DLG3 was first reported in relation to non-syndromic X-linked intellectual disability in 2004 (Tarpey et al., PMID: 15185169). Affected males present with intellectual disability of variable severity, without other consistent clinical manifestations.
Nine variants (splice, frameshift, nonsense and 5’ UTR variant that interfered with protein translation) that have been reported in nine probands in five publications (PMIDs: 15185169, 19795139, 24721225, 25649377, 2722290) are included in this curation. Variants in this gene segregated with disease in additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function (PMID: 15185169).
This gene-disease relationship is also supported by a mouse model and protein interactions. DLG3 encodes a member of the membrane-associated guanylate kinase (MAGUK) protein family. MAGUK proteins play a major role in the organization of receptors and in downstream signaling pathways in the synapse. DLG3 localizes to the postsynaptic density of excitatory synapses, where it interacts with NMDA glutamate receptors.
In summary, there is definitive evidence supporting the relationship between DLG3 and non-syndromic X-linked intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 24, 2018 (SOP Version 5). As of September 2025, this record underwent administrative updates to edit the evidence summary text and update scoring to be consistent with SOP Version 11. No new evidence has been added.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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