ClinGen Dosage Sensitivity Curation Page

NLGN3

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Haploinsufficiency phenotype comments:

No clear loss of function mutations have been reported. Jamain et al (2003) reported two brothers with autism who had a maternally-inherited missense mutation in NLGN3 (R451C) (PMID: 12669065). Functional studies indicate that the protein is retained in the endoplastic reticulum but some synaptic induction activity is present (PMIDs: 15150161, 15152050, 15797875). Blasi et al (2006) found a maternally-inherited non-synonymous sequence change in brothers with autism that was also found in multiple controls (PMID: 16508939) and Talebizadeh et al (2006) reported 9 of 10 autistic females had an aberrant splice variant that was also found in normal individuals and no mutations were identified. Ylisaukko-oja et al. (2005) reported a modest association between NLGN3 and autism but failed to find any mutations in 100 families (PMID: 16077734). Several additional studies screened individuals with autism and found no mutations (PMID;15622415, 18189281, 15274046, and 15389766).

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 score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

No focal duplications of NLGN3 have been reported. Kaya et al (2012) report a family with a large duplication at Xq12q13.3 that segregates with autism in three males. Female carriers are normal. However, the duplication contains 139 genes total and the authors speculate on the effect of duplication of NLGN3 (PMID: 22213401).

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.