Human Gene Module / Chromosome 17 / NLGN2

NLGN2Neuroligin 2

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
4 / 8
Rare Variants / Common Variants
5 / 0
EAGLE Score
3
Limited Learn More
Aliases
-
Associated Syndromes
-
Chromosome Band
17p13.1
Associated Disorders
-
Genetic Category
Rare Single Gene Mutation, Functional
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 neuroligin2 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
c.644G>A p.Arg215His missense_variant Unknown - Simplex 21551456 Sun C , et al. (2011)
c.1342C>T p.Arg448Cys missense_variant De novo NA - 25363760 De Rubeis S , et al. (2014)
c.1956G>T p.Glu652Asp missense_variant De novo NA Simplex 28714951 Lim ET , et al. (2017)
c.988C>T p.Arg330Cys missense_variant De novo NA Simplex 25961944 Krumm N , et al. (2015)
c.441C>A p.Tyr147Ter stop_gained De novo NA Multi-generational 27865048 Parente DJ , et al. (2016)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

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.

Score Delta: Score remained at 4

1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

10/1/2019
4
icon
1

Decreased from 4 to 1

New Scoring Scheme
Description

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.

Reports Added
[New Scoring Scheme]
10/1/2017
icon
4

Increased from to 4

Description

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: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
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 exac.broadinstitute.org. 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: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle 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 www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
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.
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