Human Gene Module / Chromosome 17 / NLGN2

NLGN2Neuroligin 2

Minimal Evidence Criteria 4.1
Autism Reports / Total Reports
4 / 8
Rare Variants / Common Variants
5 / 0
Associated Syndromes
Genetic Category
Rare Single Gene Mutation, Functional
Chromosome Band
Associated Disorders
Relevance to Autism

Nlgn2(-/-) mice displayed reduced exploratory activity, impaired rotarod performance, and delays on several developmental milestones, whereas Nlgn2(-/-) pups isolated from mother and littermates emitted fewer ultrasonic vocalizations and spent less time calling than Nlgn2(+/+) littermate controls (Wohr et al., 2013).

Molecular Function

Transmembrane scaffolding protein involved in cell-cell interactions via its interactions with neurexin family members. Plays a role in synapse function and synaptic signal transmission, especially via gamma-aminobutyric acid receptors (GABA(A) receptors), by recruiting and clustering synaptic proteins. Modulates signaling by inhibitory synapses, and thereby plays a role in controlling the ratio of signaling by excitatory and inhibitory synapses and information processing.

Reports related to NLGN2 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Identification and functional characterization of rare mutations of the neuroligin-2 gene (NLGN2) associated with schizophrenia. Sun C , et al. (2011) No -
2 Primary Developmental delays and reduced pup ultrasonic vocalizations but normal sociability in mice lacking the postsynaptic cell adhesion protein neuroli... Whr M , et al. (2012) No -
3 Support Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
4 Support Excess of rare, inherited truncating mutations in autism. Krumm N , et al. (2015) Yes -
5 Support Neuroligin 2 nonsense variant associated with anxiety, autism, intellectual disability, hyperphagia, and obesity. Parente DJ , et al. (2016) Yes Anxiety, obsessive-compulsive behaviors, obesity,
6 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Lim ET , et al. (2017) Yes -
7 Support Neuroligin 2 R215H Mutant Mice Manifest Anxiety, Increased Prepulse Inhibition, and Impaired Spatial Learning and Memory. Chen CH , et al. (2017) No -
8 Support GABAergic deficits and schizophrenia-like behaviors in a mouse model carrying patient-derived neuroligin-2 R215H mutation. Jiang DY , et al. (2018) No -
Rare Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
G>T p.Glu652Asp missense_variant De novo - - 28714951 Lim ET , et al. (2017)
c.1342C>T p.Arg448Cys missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.644G > A p.Arg215His missense_variant Unknown - Simplex 21551456 Sun C , et al. (2011)
c.988C>T p.Arg330Cys missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.441C>A p.Tyr147Ter stop_gained De novo - Multi-generational 27865048 Parente DJ , et al. (2016)
Common Variants  

No common variants reported.

SFARI Gene score

Minimal Evidence


Score Delta: Score remained at 4.4


Minimal Evidence

See all Category 4 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as 'acc" in the score cards) could also boost a gene from category 4 to 3.


Increased from to 4


Nlgn2(-/-) mice were shown to display reduced exploratory activity, impaired rotarod performance, and delays on several developmental milestones, whereas Nlgn2(-/-) pups isolated from mother and littermates emitted fewer ultrasonic vocalizations and spent less time calling than Nlgn2(+/+) littermate controls (Wohr et al., 2013). De novo missense variants in the NLGN2 gene have been observed in ASD probands (De Rubeis et al., 2014; Krumm et al., 2015; Lim et al., 2017). A de novo nonsense variant in NLGN2 was identified in a 15-year-old boy diagnosed with autism (PDD-NOS) and presenting with intellectual disability, behavioral abnormalities, obesity, macrocephaly, and dysmorphic features (Parente et al., 2017); however, the patient's family history was positive for ADHD, OCD, learning disability, and dyslexia.

Krishnan Probability Score

Score 0.49034855015661

Ranking 6159/25841 scored genes

[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at
ExAC Score

Score 0.99262470034397

Ranking 1680/18225 scored genes

[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: aned_exac_nonTCGA_z_pli_rec_null_data.txt
Sanders TADA Score

Score 0.8070190682722

Ranking 2336/18665 scored genes

[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see
Zhang D Score

Score 0.19033160736054

Ranking 4419/20870 scored genes

[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
CNVs associated with NLGN2(1 CNVs)
17p13.1 26 Deletion-Duplication 40  /  153
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