Human Gene Module / Chromosome 11 / NRXN2

NRXN2neurexin 2

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
12 / 18
Rare Variants / Common Variants
31 / 1
EAGLE Score
7
Moderate Learn More
Aliases
NRXN2, FLJ40892,  KIAA0921
Associated Syndromes
-
Chromosome Band
11q13.1
Associated Disorders
-
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association, Functional
Relevance to Autism

Rare mutations in the NRXN2 gene have been identified with ASD (Gauthier et al., 2011).

Molecular Function

This gene encodes a member of the neurexin gene family. The products of these genes function as cell adhesion molecules and receptors in the vertebrate nervous system. These genes utilize two promoters. The majority of transcripts are produced from the upstream promoter and encode alpha-neurexin isoforms while a smaller number of transcripts are produced from the downstream promoter and encode beta-neurexin isoforms.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome Informatics
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to NRXN2 (18 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia Gauthier J , et al. (2011) Yes -
2 Support Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders Cukier HN , et al. (2014) Yes -
3 Recent Recommendation Targeted combinatorial alternative splicing generates brain region-specific repertoires of neurexins Schreiner D , et al. (2014) No -
4 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No Stereotypic behavior
5 Recent Recommendation Genetic targeting of NRXN2 in mice unveils role in excitatory cortical synapse function and social behaviors Born G , et al. (2015) No -
6 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
7 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
8 Positive Association Neurexin gene family variants as risk factors for autism spectrum disorder Wang J , et al. (2017) Yes -
9 Support A de novo 921 Kb microdeletion at 11q13.1 including neurexin 2 in a boy with developmental delay, deficits in speech and language without autistic behaviors Yuan H , et al. (2018) No -
10 Support Genomic landscapes of Chinese sporadic autism spectrum disorders revealed by whole-genome sequencing Wu J , et al. (2018) Yes -
11 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
12 Support - Bertoli-Avella AM et al. (2021) No -
13 Support - Bruno LP et al. (2021) Yes -
14 Support - Zhou X et al. (2022) Yes -
15 Support - Haile MT et al. (2023) Yes -
16 Support - Hu C et al. (2023) Yes -
17 Support - Sheth F et al. (2023) Yes DD, ID, epilepsy/seizures
18 Support - Hamide Betul Gerik-Celebi et al. () No Epilepsy/seizures
Rare Variants   (31)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - Simplex 29654904 Yuan H , et al. (2018)
c.1600C>A p.Gln534Lys missense_variant Unknown - - 37007974 Hu C et al. (2023)
c.1500C>T p.Pro500%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.598G>A p.Ala200Thr missense_variant Familial - - 21424692 Gauthier J , et al. (2011)
c.803G>T p.Gly268Val missense_variant Familial - - 21424692 Gauthier J , et al. (2011)
c.797C>T p.Ser266Phe missense_variant Familial Maternal - 37007974 Hu C et al. (2023)
c.1888G>A p.Gly630Ser missense_variant Familial - - 21424692 Gauthier J , et al. (2011)
c.1964T>C p.Val655Ala missense_variant Familial - - 21424692 Gauthier J , et al. (2011)
c.2413C>T p.Pro805Ser missense_variant Familial - - 21424692 Gauthier J , et al. (2011)
c.2441C>T p.Ala814Val missense_variant Familial - - 21424692 Gauthier J , et al. (2011)
c.1795G>A p.Gly599Ser missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.2904G>C p.Arg968Ser missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.3091C>G p.Arg1031Gly missense_variant Familial - - 21424692 Gauthier J , et al. (2011)
c.3241G>A p.Asp1081Asn missense_variant Familial - - 21424692 Gauthier J , et al. (2011)
c.3250C>T p.His1084Tyr missense_variant Familial - - 21424692 Gauthier J , et al. (2011)
c.5087C>A p.Pro1696His missense_variant Familial - - 21424692 Gauthier J , et al. (2011)
c.3526G>A p.Ala1176Thr missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2442G>A p.Ala814= synonymous_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.876C>G p.Phe292Leu missense_variant De novo - Simplex 34948243 Bruno LP et al. (2021)
c.4189C>T p.Leu1397%3D synonymous_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.4253-512del - frameshift_variant De novo - Simplex 33875846 Bertoli-Avella AM et al. (2021)
c.4296C>A p.Asp1432Glu missense_variant Unknown - - 38739110 Hamide Betul Gerik-Celebi et al. ()
c.1799G>T p.Gly600Val missense_variant Familial Maternal Simplex 37543562 Sheth F et al. (2023)
c.809_810insG p.Gly271ArgfsTer26 frameshift_variant De novo - Simplex 30392784 Wu J , et al. (2018)
c.1901G>T p.Gly634Val missense_variant Familial Maternal - 38739110 Hamide Betul Gerik-Celebi et al. ()
c.3651del p.Asn1217LysfsTer3 frameshift_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.2734del p.Leu912CysfsTer76 frameshift_variant Familial Paternal Simplex 21424692 Gauthier J , et al. (2011)
c.808dup p.Ala270GlyfsTer27 frameshift_variant Familial Maternal - 38739110 Hamide Betul Gerik-Celebi et al. ()
c.808dup p.Ala270GlyfsTer27 frameshift_variant Familial Paternal - 38739110 Hamide Betul Gerik-Celebi et al. ()
c.1814G>A p.Arg605Gln missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1090G>A p.Val364Ile missense_variant Familial - Extended multiplex (at least one pair of ASD affec 24410847 Cukier HN , et al. (2014)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.242T>A p.Leu81Gln missense_variant - - - 29045040 Wang J , et al. (2017)
SFARI Gene score
1

High Confidence

A study sequenced NRXN2 in 142 ASD patients and found a single truncating mutation in an ASD patient that was inherited from a father with severe language delay (PMID 21424692). This family was also linked to SCZ. Another study found a single patient with autistic traits, dysmorphism, cancer and a de novo deletion involving NRXN2 and other genes (including MEN1) (PMID 21600320).

Score Delta: Score remained at 1

criteria met
See SFARI Gene'scoring criteria
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.

4/1/2021
1
icon
1

Score remained at 1

Description

A study sequenced NRXN2 in 142 ASD patients and found a single truncating mutation in an ASD patient that was inherited from a father with severe language delay (PMID 21424692). This family was also linked to SCZ. Another study found a single patient with autistic traits, dysmorphism, cancer and a de novo deletion involving NRXN2 and other genes (including MEN1) (PMID 21600320).

Reports Added
[Combining exome/genome sequencing with data repository analysis reveals novel gene-disease associations for a wide range of genetic disorders2021]
10/1/2019
4
icon
1

Decreased from 4 to 1

New Scoring Scheme
Description

A study sequenced NRXN2 in 142 ASD patients and found a single truncating mutation in an ASD patient that was inherited from a father with severe language delay (PMID 21424692). This family was also linked to SCZ. Another study found a single patient with autistic traits, dysmorphism, cancer and a de novo deletion involving NRXN2 and other genes (including MEN1) (PMID 21600320).

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

A study sequenced NRXN2 in 142 ASD patients and found a single truncating mutation in an ASD patient that was inherited from a father with severe language delay (PMID 21424692). This family was also linked to SCZ. Another study found a single patient with autistic traits, dysmorphism, cancer and a de novo deletion involving NRXN2 and other genes (including MEN1) (PMID 21600320).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
10/1/2018
4
icon
4

Decreased from 4 to 4

Description

A study sequenced NRXN2 in 142 ASD patients and found a single truncating mutation in an ASD patient that was inherited from a father with severe language delay (PMID 21424692). This family was also linked to SCZ. Another study found a single patient with autistic traits, dysmorphism, cancer and a de novo deletion involving NRXN2 and other genes (including MEN1) (PMID 21600320).

Reports Added
[Genomic landscapes of Chinese sporadic autism spectrum disorders revealed by whole-genome sequencing.2018]
10/1/2017
4
icon
4

Decreased from 4 to 4

Description

A study sequenced NRXN2 in 142 ASD patients and found a single truncating mutation in an ASD patient that was inherited from a father with severe language delay (PMID 21424692). This family was also linked to SCZ. Another study found a single patient with autistic traits, dysmorphism, cancer and a de novo deletion involving NRXN2 and other genes (including MEN1) (PMID 21600320).

Reports Added
[Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.2017] [Neurexin gene family variants as risk factors for autism spectrum disorder.2017]
7/1/2017
4
icon
4

Decreased from 4 to 4

Description

A study sequenced NRXN2 in 142 ASD patients and found a single truncating mutation in an ASD patient that was inherited from a father with severe language delay (PMID 21424692). This family was also linked to SCZ. Another study found a single patient with autistic traits, dysmorphism, cancer and a de novo deletion involving NRXN2 and other genes (including MEN1) (PMID 21600320).

Reports Added
[Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.2017]
4/1/2015
4
icon
4

Decreased from 4 to 4

Description

A study sequenced NRXN2 in 142 ASD patients and found a single truncating mutation in an ASD patient that was inherited from a father with severe language delay (PMID 21424692). This family was also linked to SCZ. Another study found a single patient with autistic traits, dysmorphism, cancer and a de novo deletion involving NRXN2 and other genes (including MEN1) (PMID 21600320).

Reports Added
[Genetic targeting of NRXN2 in mice unveils role in excitatory cortical synapse function and social behaviors.2015]
1/1/2015
4
icon
4

Decreased from 4 to 4

Description

A study sequenced NRXN2 in 142 ASD patients and found a single truncating mutation in an ASD patient that was inherited from a father with severe language delay (PMID 21424692). This family was also linked to SCZ. Another study found a single patient with autistic traits, dysmorphism, cancer and a de novo deletion involving NRXN2 and other genes (including MEN1) (PMID 21600320).

Reports Added
[Large-scale discovery of novel genetic causes of developmental disorders.2014]
10/1/2014
4
icon
4

Decreased from 4 to 4

Description

A study sequenced NRXN2 in 142 ASD patients and found a single truncating mutation in an ASD patient that was inherited from a father with severe language delay (PMID 21424692). This family was also linked to SCZ. Another study found a single patient with autistic traits, dysmorphism, cancer and a de novo deletion involving NRXN2 and other genes (including MEN1) (PMID 21600320).

Reports Added
[Targeted combinatorial alternative splicing generates brain region-specific repertoires of neurexins.2014]
7/1/2014
No data
icon
4

Increased from No data to 4

Description

A study sequenced NRXN2 in 142 ASD patients and found a single truncating mutation in an ASD patient that was inherited from a father with severe language delay (PMID 21424692). This family was also linked to SCZ. Another study found a single patient with autistic traits, dysmorphism, cancer and a de novo deletion involving NRXN2 and other genes (including MEN1) (PMID 21600320).

4/1/2014
No data
icon
4

Increased from No data to 4

Description

A study sequenced NRXN2 in 142 ASD patients and found a single truncating mutation in an ASD patient that was inherited from a father with severe language delay (PMID 21424692). This family was also linked to SCZ. Another study found a single patient with autistic traits, dysmorphism, cancer and a de novo deletion involving NRXN2 and other genes (including MEN1) (PMID 21600320).

Krishnan Probability Score

Score 0.59146003441086

Ranking 476/25841 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.
Original Source
ExAC Score

Score 0.99989557401525

Ranking 682/18225 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
Original Source
Sanders TADA Score

Score 0.92490568610906

Ranking 10091/18665 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).
Original Source
Larsen Cumulative Evidence Score

Score 21

Ranking 100/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.007170651562193

Ranking 8451/20870 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.
Original Source
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