Human Gene Module / Chromosome 14 / NRXN3

NRXN3neurexin 3

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
9 / 18
Rare Variants / Common Variants
21 / 5
Aliases
NRXN3, C14orf60
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Genetic Association
Chromosome Band
14q24.3-q31.1
Associated Disorders
EPS, SCZ, ID, ADHD
Relevance to Autism

Rare mutations in the NRXN3 gene, including deletions and missense variants, have been identified in patients with ASD (Vaags et al., 2012).

Molecular Function

Neurexins are a family of proteins that function in the vertebrate nervous system as cell adhesion molecules and receptors. NRXN3 is one of the largest known human genes. It utilizes two alternate promoters and includes numerous alternatively spliced exons to generate thousands of distinct mRNA transcripts and protein isoforms. The majority of transcripts are produced from the upstream promoter and encode alpha-neurexin isoforms; a much smaller number of transcripts are produced from the downstream promoter and encode beta-neurexin isoforms.

Reports related to NRXN3 (18 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Rare deletions at the neurexin 3 locus in autism spectrum disorder Vaags AK , et al. (2012) Yes -
2 Support A discovery resource of rare copy number variations in individuals with autism spectrum disorder Prasad A , et al. (2013) Yes -
3 Positive Association Association study of NRXN3 polymorphisms with schizophrenia and risperidone-induced bodyweight gain in Chinese Han population Hu X , et al. (2013) No -
4 Support Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder Girirajan S , et al. (2013) Yes -
5 Positive Association Genetic study of neurexin and neuroligin genes in Alzheimer's disease Martinez-Mir A , et al. (2013) No -
6 Support Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature Bna F , et al. (2013) Yes Epilepsy
7 Recent Recommendation Presynaptic neurexin-3 alternative splicing trans-synaptically controls postsynaptic AMPA receptor trafficking Aoto J , et al. (2013) No -
8 Support Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families Egger G , et al. (2014) Yes -
9 Recent Recommendation Targeted combinatorial alternative splicing generates brain region-specific repertoires of neurexins Schreiner D , et al. (2014) No -
10 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
11 Positive Association Phenome-wide association study (PheWAS) in EMR-linked pediatric cohorts, genetically links PLCL1 to speech language development and IL5-IL13 to Eosinophilic Esophagitis Namjou B , et al. (2014) No -
12 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
13 Recent Recommendation Distinct circuit-dependent functions of presynaptic neurexin-3 at GABAergic and glutamatergic synapses Aoto J , et al. (2015) No -
14 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies Redin C , et al. (2016) No Low-normal cognitive ability
15 Support Lessons learned from additional research analyses of unsolved clinical exome cases Eldomery MK , et al. (2017) No -
16 Positive Association Neurexin gene family variants as risk factors for autism spectrum disorder Wang J , et al. (2017) Yes -
17 Support A rare exonic NRXN3 deletion segregating with neurodevelopmental and neuropsychiatric conditions in a three-generation Chinese family Yuan H , et al. (2018) Yes ID, ADHD, SCZ
18 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
Rare Variants   (21)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo NA - 27841880 Redin C , et al. (2016)
- - copy_number_loss De novo NA - 23533028 Bna F , et al. (2013)
- - copy_number_loss Unknown - - 24643514 Egger G , et al. (2014)
- - copy_number_loss De novo NA - 22209245 Vaags AK , et al. (2012)
- - copy_number_loss Unknown - Unknown 23275889 Prasad A , et al. (2013)
c.3142+3A>G - splice_site_variant - - - 28327206 Eldomery MK , et al. (2017)
c.196A>G p.Lys66Glu missense_variant - - - 28327206 Eldomery MK , et al. (2017)
- - copy_number_loss Familial Maternal Simplex 22209245 Vaags AK , et al. (2012)
- - copy_number_loss Familial Maternal Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_loss Familial Paternal Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_loss Familial - Multi-generational 30076746 Yuan H , et al. (2018)
- - copy_number_loss Familial Paternal Multiplex 22209245 Vaags AK , et al. (2012)
- - copy_number_loss Familial Paternal Simplex 23375656 Girirajan S , et al. (2013)
c.673G>A p.Glu225Lys missense_variant De novo NA - 25363760 De Rubeis S , et al. (2014)
- - copy_number_loss Familial Paternal Multi-generational 22209245 Vaags AK , et al. (2012)
c.3118G>A p.Gly1040Arg missense_variant Familial Maternal - 22209245 Vaags AK , et al. (2012)
c.19G>A p.Ala7Thr missense_variant Familial Maternal Simplex 22209245 Vaags AK , et al. (2012)
c.128G>A p.Trp43Ter missense_variant Familial Paternal Simplex 22209245 Vaags AK , et al. (2012)
c.1219C>T p.Arg407Trp missense_variant Familial Maternal Simplex 22209245 Vaags AK , et al. (2012)
c.2063A>G p.Tyr688Cys missense_variant De novo NA Multiplex (monozygotic twins) 31398340 Ruzzo EK , et al. (2019)
c.324C>T p.Ser108= synonymous_variant De novo NA Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.-363+67456C>A;c.769+170643C>A;c.757+173474C>A A>C intron_variant - - - 23306218 Hu X , et al. (2013)
c.-363+72677T>C;c.770-168565T>C;c.758-168565T>C C>T intron_variant - - - 23306218 Hu X , et al. (2013)
c.926-44127T>C;c.2081-44127T>C;c.2069-44127T>C;c.2045-44127T>C C>T intron_variant - - - 23306218 Hu X , et al. (2013)
c.248-34110C>T;c.2144-34110C>T;c.3299-34110C>T;c.3287-34110C>T;c.3263-34110C>T Minor allele, C intron_variant - - - 25477900 Namjou B , et al. (2014)
c.*1825G>T - 3_prime_UTR_variant - - - 29045040 Wang J , et al. (2017)
SFARI Gene score
1

High Confidence

Exonic deletions affecting the NRXN3 gene were identified in four ASD cases; the frequency of such deletions in cases (4/4,322) was found to be significantly higher than in controls (4/15,122; p=0.039). Furthermore, three of the four deletions observed in ASD cases affected both isoforms of NRXN3, whereas none in controls did so (p=0.0055). However, NRXN3 deletions showed incomplete segregation with ASD in some families, and while exonic NRXN3 deletions are likely to have a functional effect, the precise nature of that effect is unknown. (PMID 22209245)

Score Delta: Score remained at 3

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
3
icon
1

Decreased from 3 to 1

New Scoring Scheme
Description

Exonic deletions affecting the NRXN3 gene were identified in four ASD cases; the frequency of such deletions in cases (4/4,322) was found to be significantly higher than in controls (4/15,122; p=0.039). Furthermore, three of the four deletions observed in ASD cases affected both isoforms of NRXN3, whereas none in controls did so (p=0.0055). However, NRXN3 deletions showed incomplete segregation with ASD in some families, and while exonic NRXN3 deletions are likely to have a functional effect, the precise nature of that effect is unknown. (PMID 22209245)

Reports Added
[New Scoring Scheme]
7/1/2019
3
icon
3

Decreased from 3 to 3

Description

Exonic deletions affecting the NRXN3 gene were identified in four ASD cases; the frequency of such deletions in cases (4/4,322) was found to be significantly higher than in controls (4/15,122; p=0.039). Furthermore, three of the four deletions observed in ASD cases affected both isoforms of NRXN3, whereas none in controls did so (p=0.0055). However, NRXN3 deletions showed incomplete segregation with ASD in some families, and while exonic NRXN3 deletions are likely to have a functional effect, the precise nature of that effect is unknown. (PMID 22209245)

7/1/2018
icon
3

Increased from to 3

Description

Exonic deletions affecting the NRXN3 gene were identified in four ASD cases; the frequency of such deletions in cases (4/4,322) was found to be significantly higher than in controls (4/15,122; p=0.039). Furthermore, three of the four deletions observed in ASD cases affected both isoforms of NRXN3, whereas none in controls did so (p=0.0055). However, NRXN3 deletions showed incomplete segregation with ASD in some families, and while exonic NRXN3 deletions are likely to have a functional effect, the precise nature of that effect is unknown. (PMID 22209245)

4/1/2018
3
icon

Decreased from 3 to

Description

3

10/1/2017
3
icon
3

Decreased from 3 to 3

Description

Exonic deletions affecting the NRXN3 gene were identified in four ASD cases; the frequency of such deletions in cases (4/4,322) was found to be significantly higher than in controls (4/15,122; p=0.039). Furthermore, three of the four deletions observed in ASD cases affected both isoforms of NRXN3, whereas none in controls did so (p=0.0055). However, NRXN3 deletions showed incomplete segregation with ASD in some families, and while exonic NRXN3 deletions are likely to have a functional effect, the precise nature of that effect is unknown. (PMID 22209245)

4/1/2017
3
icon
3

Decreased from 3 to 3

Description

Exonic deletions affecting the NRXN3 gene were identified in four ASD cases; the frequency of such deletions in cases (4/4,322) was found to be significantly higher than in controls (4/15,122; p=0.039). Furthermore, three of the four deletions observed in ASD cases affected both isoforms of NRXN3, whereas none in controls did so (p=0.0055). However, NRXN3 deletions showed incomplete segregation with ASD in some families, and while exonic NRXN3 deletions are likely to have a functional effect, the precise nature of that effect is unknown. (PMID 22209245)

Reports Added
[Genetic study of neurexin and neuroligin genes in Alzheimer's disease.2013] [Rare deletions at the neurexin 3 locus in autism spectrum disorder.2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families.2014] [Phenome-wide association study (PheWAS) in EMR-linked pediatric cohorts, genetically links PLCL1 to speech language development and IL5-IL13 to Eos...2014] [Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature.2013] [Association study of NRXN3 polymorphisms with schizophrenia and risperidone-induced bodyweight gain in Chinese Han population.2013] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Presynaptic neurexin-3 alternative splicing trans-synaptically controls postsynaptic AMPA receptor trafficking.2013] [Targeted combinatorial alternative splicing generates brain region-specific repertoires of neurexins.2014] [Distinct circuit-dependent functions of presynaptic neurexin-3 at GABAergic and glutamatergic synapses.2015] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016] [Lessons learned from additional research analyses of unsolved clinical exome cases.2017]
10/1/2016
3
icon
3

Decreased from 3 to 3

Description

Exonic deletions affecting the NRXN3 gene were identified in four ASD cases; the frequency of such deletions in cases (4/4,322) was found to be significantly higher than in controls (4/15,122; p=0.039). Furthermore, three of the four deletions observed in ASD cases affected both isoforms of NRXN3, whereas none in controls did so (p=0.0055). However, NRXN3 deletions showed incomplete segregation with ASD in some families, and while exonic NRXN3 deletions are likely to have a functional effect, the precise nature of that effect is unknown. (PMID 22209245)

1/1/2016
3
icon
3

Decreased from 3 to 3

Description

Exonic deletions affecting the NRXN3 gene were identified in four ASD cases; the frequency of such deletions in cases (4/4,322) was found to be significantly higher than in controls (4/15,122; p=0.039). Furthermore, three of the four deletions observed in ASD cases affected both isoforms of NRXN3, whereas none in controls did so (p=0.0055). However, NRXN3 deletions showed incomplete segregation with ASD in some families, and while exonic NRXN3 deletions are likely to have a functional effect, the precise nature of that effect is unknown. (PMID 22209245)

4/1/2015
3
icon
3

Decreased from 3 to 3

Description

Exonic deletions affecting the NRXN3 gene were identified in four ASD cases; the frequency of such deletions in cases (4/4,322) was found to be significantly higher than in controls (4/15,122; p=0.039). Furthermore, three of the four deletions observed in ASD cases affected both isoforms of NRXN3, whereas none in controls did so (p=0.0055). However, NRXN3 deletions showed incomplete segregation with ASD in some families, and while exonic NRXN3 deletions are likely to have a functional effect, the precise nature of that effect is unknown. (PMID 22209245)

1/1/2015
3
icon
3

Decreased from 3 to 3

Description

Exonic deletions affecting the NRXN3 gene were identified in four ASD cases; the frequency of such deletions in cases (4/4,322) was found to be significantly higher than in controls (4/15,122; p=0.039). Furthermore, three of the four deletions observed in ASD cases affected both isoforms of NRXN3, whereas none in controls did so (p=0.0055). However, NRXN3 deletions showed incomplete segregation with ASD in some families, and while exonic NRXN3 deletions are likely to have a functional effect, the precise nature of that effect is unknown. (PMID 22209245)

10/1/2014
3
icon
3

Decreased from 3 to 3

Description

Exonic deletions affecting the NRXN3 gene were identified in four ASD cases; the frequency of such deletions in cases (4/4,322) was found to be significantly higher than in controls (4/15,122; p=0.039). Furthermore, three of the four deletions observed in ASD cases affected both isoforms of NRXN3, whereas none in controls did so (p=0.0055). However, NRXN3 deletions showed incomplete segregation with ASD in some families, and while exonic NRXN3 deletions are likely to have a functional effect, the precise nature of that effect is unknown. (PMID 22209245)

7/1/2014
icon
3

Increased from to 3

Description

Exonic deletions affecting the NRXN3 gene were identified in four ASD cases; the frequency of such deletions in cases (4/4,322) was found to be significantly higher than in controls (4/15,122; p=0.039). Furthermore, three of the four deletions observed in ASD cases affected both isoforms of NRXN3, whereas none in controls did so (p=0.0055). However, NRXN3 deletions showed incomplete segregation with ASD in some families, and while exonic NRXN3 deletions are likely to have a functional effect, the precise nature of that effect is unknown. (PMID 22209245)

Krishnan Probability Score

Score 0.76535427628994

Ranking 23/25841 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 0.99985550075577

Ranking 734/18225 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 0.95060540895693

Ranking 18558/18665 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).
Larsen Cumulative Evidence Score

Score 11

Ranking 173/461 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.
Zhang D Score

Score 0.52671919280822

Ranking 347/20870 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.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
CG12374 CG12374 gene product from transcript CG12374-RA Fruit Fly Protein Binding 36410 Q7JYV3
CG15576 CG15576 gene product from transcript CG15576-RB Fruit Fly Protein Binding 31369 Q9W4M0
CG33123 CG33123 gene product from transcript CG33123-RB Fruit Fly Protein Binding 326262 Q9VQR8
CG7102 CG7102 gene product from transcript CG7102-RB Fruit Fly Protein Binding 34079 Q9VLV6
FKBP59 FK506-binding protein FKBP59 Fruit Fly Protein Binding 47762 Q9VL78
Gbs-70E Glycogen binding subunit 70E Fruit Fly Protein Binding 39588 Q8SWT8
GPR183 G-protein coupled receptor 183 Human Protein Binding 1880 P32249
Rfabg Retinoid- and fatty acid-binding glycoprotein Fruit Fly Protein Binding 43827 L0MPS3
TpnC4 Troponin C isoform 4 Fruit Fly Protein Binding 35498 Q7K860
vtd verthandi Fruit Fly Protein Binding 3354896 A0A021WW32
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