DLG3

Gene Facts

• HGNC Symbol: DLG3 (HGNC:2902)
• HGNC Name: discs large MAGUK scaffold protein 3
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: NE-Dlg, SAP102, SAP-102, NEDLG, KIAA1232, MRX90, PPP1R82
• %HI: 14.46
• pLI: 1
• LOEUF: 0.09
• Cytoband: Xq13.1
• Genomic Coordinates:

  GRCh37/hg19:	chrX:69664685-69725340
  GRCh38/hg38:	chrX:70444835-70505490

• MANE Select Transcript: NM_021120.4 ENST00000374360.8
• Function: Required for learning most likely through its role in synaptic plasticity following NMDA receptor signaling. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-4030
• ClinGen Curation ID: CCID:006996
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 04/25/2024

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• non-syndromic X-linked intellectual disability

HI Evidence

• PUBMED: 15185169
  Tarpey et al. (2004 - Am J Hum Genet) describe 4 different truncating variants (3 frameshift and 1 nonsense) in 4 unrelated families with moderate to severe nonsyndromic X-linked intellectual disability. In Fig 1, family A had 4 affected males (including proband), 3 obligate carrier females, and one mildly affected female; family B had 4 affected males (including proband) and 2 obligate carriers; family C had 2 affected males and one obligate carrier mother; and family D had 4 affected males and one obligate carrier female . These changes were not found in 350 control chromosomes. Where possible, X-inactivation pattern in lymphocytes and carrier status/clinical manifestation in females did not show a correlation . Overall, identification of four mutations in 4 (1.2%) of 329 families suggests DLG3 makes a significant contribution to the etiology of XL-intellectual disability
• PUBMED: 19795139
  Zanni et al. (2010 - Neurogenetics) describe a novel splice acceptor-site sequence variant in intron 6 segregating within a Flemish family with nonsyndromic X-linked intellectual disability. This variant introduces a frameshift and a premature stop codon at position 357 of the SAP102 protein encoded by DLG3. It was observed in 3 affected males and 1 obligate carrier female (pedigree. Fig. 1). This mutation was not seen in 160 control X-chromosomes.
• PUBMED: 24721225
  Philips et al. 2014 (Orphanet J Rare Dis) described 3 affected males and 2 obligate carrier females from one family and 5 affected males and 2 obligate carrier females from a second unrelated family; both of Finnish descent identified by WES (see pedigree in figure 3). In the first family, donor splice site variant, DLG3:c.357 + 1G > C, was identified. All males presented with mild to moderate ID, narrow thorax, molar hypoplasia, short up-slanting palpebral fissures, strabismus, and hypotonia. All female carriers of the DLG3:c.357 + 1G > C were of normal intelligence with no cognitive or memory problems. X-inactivation in lymphocytes showed a normal pattern. In the second family with 5 affected males, a different donor splice site mutation was identified, c.985 + 1G > C, in DLG3. All males experienced delayed motor and language development. Three males had strabismus and attention deficit hyperactivity disorder, two exhibited bifid uvula, and one experienced seizures in childhood. Cognitive performance in affected males varied from severe to moderate ID. The 2 obligate carrier females exhibited a skewed X-inactivation pattern.
• PUBMED: 32021600
  Sandestig et al., Mol Syndromol. 2020 - male with a c.1720C>T, (p.Arg574*) variant. Phenotypic features reported were intellectual disability, attention deficit, and hyperactive behavior, an outgoing personality. Delayed motor and speech development, short stature due to growth hormone deficiency, dysmorphic features, and pectus excavatum. The child's mother was a heterozygous carrier of the same variant and presented with learning disability and borderline cognitive development; X-inactivation studies were noninformative.
• PUBMED: 25644381
  Hu et al., (Mol Psychiatry. 2016) identified 2 patients in X-linked intellectual disability cohort, both with DLG3 frameshifts. This was reported in Supplemental table 1.

• HI Evidence Comments: DLG3 is the first X-linked ID gene directly linked to glutamate receptor signaling. This is recognized as an important mechanism in regulating synaptic formation and plasticity in brain development (PMID: 19795139). Of note, loss-of-function mutations in the SAP102 (dlg3/dlgh3/NE-dlg gene in a mouse knockout model) cause nonsyndromic X-linked intellectual disability. Additional mouse genetic studies show that loss-of-function of one of the associated post-synaptic proteins results in impairment in the hippocampus (spatial learning deficits, spinal cord, cortex, and striatum) (PMID: 17344405). Additional Evidence Includes: PMID: 25649377- Tzschach et al., in Eur J Hum Genet, 2015 describe a male with a maternal nonsense variant in DLG3 (initially reported in Leiden open variation database with intellectual disability, details on phenotype not provided). Variant ID: 36894, see Table 1 PMID: 27222290 - Kumar et al., in Eur J Hum Genet. 2016 reported a DLG3 5ʹ-UTR single nucleotide duplication in a multi-generation family among affected males. PMID: 28777483, Gieldon et al., Am J Med Genet A. 2017 – one 12-year-old male index patient had moderate intellectual disability and dysmorphic features. The DLG3 variant was a nonsense variant. PMID: 32776513, Zhang et al., Ann Hum Genet. 2020 - a male with developmental delay and cognitive impairment. c.905-2A>G intronic DLG3 variant. The individual's clinical features were not further described; however, the variant resulted in multiple transcripts. No other variants were identified in the individual. PMID: 33739554, Taskiran et al., J Intellect Disabil Res. 2021 - two male siblings with moderate to severe intellectual disability, language and motor delays, and cerebellar ataxia and atrophy. c.1486C>T in DGL3 called VUS. No other variants in those patients. Parental relationship was consanguineous. PMID: 38249294, He et al., Fron Mol Neurosci. 2024 - described 7 unrelated males with epilepsy, each with a DLG3 variant that was maternally inherited. Other phenotypic features were provided in Table 1, which included autism spectrum disorder, developmental delay, and intellectual disability (ID) in two patients; one of those patients also had speech delay; one other patient had mild ID; yet another patient had ID and speech delay. Three patients were 'normal', two of whom had the same variant (p.Gly43Val). The authors suggest that complete vs. partial loss of function cause a neurological spectrum that starts with abnormal neuronal conduction for partial loss of function variants to severe with complete loss of function.

NOTE

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: At this time no focal duplications of DLG3 have been described.

NOTE

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.