Relevance to Autism

Maternally-inherited hemizygous variants in the DLG3 gene have been identified in male ASD probands from ancestrally diverse cohorts, including ASD cohorts from China, Bulgaria, and most recently Turkey (Hu et al., 2022; Gogate et al., 2024; Belenska-Todorova et al., 2025; Eser et al., 2026), while de novo variants in this gene were previously reported in ASD probands from the SPARK and MSSNG cohorts (Zhou et al., 2022). Two of the seven males with X-linked epilepsy resulting from maternally-inherited hemizygous DLG3 missense variants described in He et al., 2024 were reported to also present with ASD. More recently, Malbos et al., 2025 described 17 novel individuals with 16 different DLG3 variants (10 with pathogenic loss-of-function and 6 variants of uncertain significance) and found that ASD was present in 1/10 individuals with a loss-of-function variant and 3/7 individuals with a variant of uncertain significance. The protein encoded by the DLG3 gene (often referred to as SAP102) has been shown to interact with proteins encoded by other ASD candidate genes, including GRIN2B (Muller et al., 1996), APC (Makino et al., 1997), SYNGAP1 (Kim et al., 1998), DLG4 (Masuko et al., 1999), ERBB4 (Garcia et al., 2000), and NBEA (Lauks et al., 2012).

Molecular Function

This gene encodes a member of the membrane-associated guanylate kinase protein family. The encoded protein may play a role in clustering of NMDA receptors at excitatory synapses. It may also negatively regulate cell proliferation through interaction with the C-terminal region of the adenomatosis polyposis coli tumor suppressor protein. Mutations in this gene have been associated with X-linked cognitive disability (X-linked intellectual developmental disorder-90, OMIM 300850).

External Links

References