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: Emerging Evidence for Haploinsufficiency (2)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 11/21/2019

Haploinsufficiency (HI) Score Details

• HI Score: 2
• HI Evidence Strength: Emerging Evidence for Haploinsufficiency

HI Disease

• intellectual disability, X-linked 90

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 Finnish 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.

• 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) Although multiple families are described for this X-linked gene with multiple males affected (over 20 including obligate carriers) which fall into category H of the new scoring rubric (maximum points 0.45 awarded), majority of these were inherited from apparently healthy mothers who were obligate carriers. There is some in vivo functional data and in silico scores (HI = 14.4/pLI = 1) suggesting moderate dosage sensitivity; compelling evidence with a large genotype-phenotype dataset is lacking. Additional papers: PMID: 25649377, Tzschach et al in EJHG, 2015 describes 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:25644381, Hu et al., Mol Psychiatry. 2016 – 1 patient reported in Supplemental table 1 DLG3 5ʹ UTR duplication in a multi-generation family among affected males (PMID: 27222290, EJHG 2016 PMID: 28777483, Am J Med Genet A. 2017 – one 12-year-old male index patient had moderate intellectual disability and dysmorphic features

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: focal duplications of DLG3 not 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.