NLGN3 was first reported in relation to X-linked complex neurodevelopmental disorder in 2003 (Jamain et al., PMID: 12669065). NLGN43 encodes a member of the neuroligin family of neuronal cell-adhesion molecules that are localized postsynaptically, interact with presynaptic neurexins, and play a key role in the maturation and function of synapses. NLGN3 variants have been identified in males with autism, intellectual disability, learning disability, or seizures. Carrier females are unaffected. Variants in NLGN3 were curated under the disease entity complex neurodevelopmental disorder. A truncating variant reported in an individual with schizophrenia (PMID: 24126926) was not included in this curation.
Four variants (nonsense, frameshift, and missense) that have been reported in five probands in four publications (PMIDs: 12669065, 25167861, 25533962, 28263302) are included in this curation. Variants in this gene segregated with disease in two additional family members. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by mouse models and in vitro functional studies that underscore a critical role of NLGN3 in synaptic transmission.
In summary, there is moderate evidence supporting the relationship between NLGN3 and X-linked complex neurodevelopmental disorder. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 15, 2018 (SOP Version 5). As of October 2025, this record underwent administrative updates to include an evidence summary text and update scoring to be consistent with SOP Version 11. No new evidence was added.
NLGN3 was first reported in relation to X-linked complex neurodevelopmental disorder in 2003 (Jamain et al., PMID: 12669065). NLGN43 encodes a member of the neuroligin family of neuronal cell-adhesion molecules that are localized postsynaptically, interact with presynaptic neurexins, and play a key role in the maturation and function of synapses. NLGN3 variants have been identified in males with autism, intellectual disability, learning disability, or seizures. Carrier females are unaffected. Variants in NLGN3 were curated under the disease entity complex neurodevelopmental disorder. A truncating variant reported in an individual with schizophrenia (PMID: 24126926) was not included in this curation.
Four variants (nonsense, frameshift, and missense) that have been reported in five probands in four publications (PMIDs: 12669065, 25167861, 25533962, 28263302) are included in this curation. Variants in this gene segregated with disease in two additional family members. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by mouse models and in vitro functional studies that underscore a critical role of NLGN3 in synaptic transmission.
In summary, there is moderate evidence supporting the relationship between NLGN3 and X-linked complex neurodevelopmental disorder. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 15, 2018 (SOP Version 5). As of October 2025, this record underwent administrative updates to include an 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).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.