Human Gene Module / Chromosome 2 / NRXN1

NRXN1neurexin 1

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
53 / 100
Rare Variants / Common Variants
1 / 4
EAGLE Score
143.75
Strong Learn More
Aliases
NRXN1, DKFZp313P2036,  FLJ35941,  Hs.22998,  KIAA0578,  PTHSL2
Associated Syndromes
Pitt-Hopkins-like syndrome 2, Tourette syndrome, Pitt-Hopkins-like syndrome 2, DD, ID, epilepsy/sei
Chromosome Band
2p16.3
Associated Disorders
SCZ, DD/NDD, ADHD, ID, EP, BPD, EPS, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association, Functional
Relevance to Autism

Recurrent mutations in the NRXN1 gene have been identified in individuals with ASD as described below. Numerous studies have demonstrated a statistically significant enrichment of NRXN1 deletions in ASD cases compared to controls [10 in 2195 cases vs. none in 2519 controls (permuted P-value 0.002) in Glessner et al., 2009; 9 in 1771 cases vs. none in 2539 controls (P-value 3.3 E-04) in Bucan et al., 2009; an excess of exonic NRNX1 CNVs in 996 cases compared to 4,964 controls ((P-value 7.7E-4) in Pinto et al., 2010; 7 exonic deletions in 2,588 cases vs. 1 in 2,670 controls (P-value 0.032) in Girirajan et al., 2013]. A similar enrichment of NRXN1 deletions have been repeatedly observed in cohorts composed of cases with a spectrum of neurodevelopmental disorders, including ASD [9 exonic NRXN1 deletions in 3,540 cases vs. 10 in 51,939 controls (P-value 8.9E-07) in Ching et al., 2010; exonic NRXN1 deletions observed in 0.11% of cases compared to 0.02% of controls (P-value 6.08E-07) in Dabell et al., 2013; NRXN1 deletions in 30 cases vs. 9 controls (simulated P-value of 0.00005) in Coe et al., 2014; P<0.0001 in 19,263 cases and 15,264 controls in Lowther et al., 2016]. Multiple studies have also reported point mutations in NRXN1 in individuals with ASD (Feng et al., 17034946; Kim et al., 2008; Yan et al., 2008; Duong et al., 2012; Liu et al., 2012; Camacho-Garcia et al., 2012), including de novo loss-of-function variants in two probands from simplex families (Iossifov et al., 2012; Stessman et al., 2017). Biallelic mutations in NRXN1 have also been implicated in Pitt-Hopkins-like syndrome 2, an autosomal recessive intellectual disability syndrome (Zweier et al., 2009; Harrison et al., 2011). A polymorphism located in the 3' UTR of NRXN1 was found to influence white matter volume and sensorimotor function in a cohort of healthy individuals in Voineskos et al., 2011 (PMID 21687627).

Molecular Function

Neurexins function in the vertebrate nervous system as cell adhesion molecules and receptors. Two neurexin genes are among the largest known in human (NRXN1 and NRXN3). By using alternate promoters, splice sites and exons, predictions of hundreds or even thousands of distinct mRNAs have been made.

SFARI Genomic Platforms
Reports related to NRXN1 (100 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Neurexin mediates the assembly of presynaptic terminals Dean C , et al. (2003) No -
2 Recent Recommendation Alternative splicing controls selective trans-synaptic interactions of the neuroligin-neurexin complex Chih B , et al. (2006) No -
3 Primary High frequency of neurexin 1beta signal peptide structural variants in patients with autism Feng J , et al. (2006) Yes -
4 Recent Recommendation Retrograde modulation of presynaptic release probability through signaling mediated by PSD-95-neuroligin Futai K , et al. (2007) No -
5 Positive Association Mapping autism risk loci using genetic linkage and chromosomal rearrangements Autism Genome Project Consortium , et al. (2007) Yes -
6 Recent Recommendation Silencing of neuroligin function by postsynaptic neurexins Taniguchi H , et al. (2007) No -
7 Recent Recommendation A patient with vertebral, cognitive and behavioural abnormalities and a de novo deletion of NRXN1alpha Zahir FR , et al. (2007) No -
8 Positive Association Disruption of neurexin 1 associated with autism spectrum disorder Kim HG , et al. (2008) Yes -
9 Positive Association Neurexin 1alpha structural variants associated with autism Yan J , et al. (2008) Yes -
10 Support Recurrent CNVs disrupt three candidate genes in schizophrenia patients Vrijenhoek T , et al. (2008) No -
11 Recent Recommendation Disruption of the neurexin 1 gene is associated with schizophrenia Rujescu D , et al. (2008) No -
12 Recent Recommendation Presynaptic targeting of alpha4beta 2 nicotinic acetylcholine receptors is regulated by neurexin-1beta Cheng SB , et al. (2009) No -
13 Recent Recommendation Mouse neurexin-1alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments Etherton MR , et al. (2009) Yes -
14 Support CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila Zweier C , et al. (2009) No ID, epilepsy
15 Recent Recommendation Sensory regulation of neuroligins and neurexin I in the honeybee brain Biswas S , et al. (2010) No -
16 Support Intragenic rearrangements in NRXN1 in three families with autism spectrum disorder, developmental delay, and speech delay Winiowiecka-Kowalnik B , et al. (2010) Yes -
17 Positive Association Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders Ching MS , et al. (2010) Yes -
18 Recent Recommendation Neurexins physically and functionally interact with GABA(A) receptors Zhang C , et al. (2010) No -
19 Support Functional impact of global rare copy number variation in autism spectrum disorders Pinto D , et al. (2010) Yes -
20 Recent Recommendation Trans-synaptic interaction of GluRdelta2 and Neurexin through Cbln1 mediates synapse formation in the cerebellum Uemura T , et al. (2010) No -
21 Recent Recommendation Splice form dependence of beta-neurexin/neuroligin binding interactions Koehnke J , et al. (2010) No -
22 Recent Recommendation Direct measure of the de novo mutation rate in autism and schizophrenia cohorts Awadalla P , et al. (2010) No -
23 Support Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia Gauthier J , et al. (2011) No ASD, ID
24 Recent Recommendation Modeling the functional genomics of autism using human neurons Konopka G , et al. (2011) No -
25 Recent Recommendation Neurexin-1 and frontal lobe white matter: an overlapping intermediate phenotype for schizophrenia and autism spectrum disorders Voineskos AN , et al. (2011) Yes SCZ
26 Recent Recommendation Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1 Gregor A , et al. (2011) No -
27 Support Compound heterozygous deletion of NRXN1 causing severe developmental delay with early onset epilepsy in two sisters Harrison V , et al. (2011) No Epilepsy
28 Support Mutations in NRXN1 in a family multiply affected with brain disorders: NRXN1 mutations and brain disorders Duong L , et al. (2012) Yes MR, Epilepsy
29 Positive Association Mutation analysis of the NRXN1 gene in a Chinese autism cohort Liu Y , et al. (2012) Yes -
30 Support Mutations affecting synaptic levels of neurexin-1? in autism and mental retardation Camacho-Garcia RJ , et al. (2012) Yes ID
31 Support De novo gene disruptions in children on the autistic spectrum Iossifov I , et al. (2012) Yes -
32 Recent Recommendation Phenotypic spectrum and genotype-phenotype correlations of NRXN1 exon deletions Schaaf CP , et al. (2012) Yes ADHD, epilepsy
33 Recent Recommendation Neuroligin-1 induces neurite outgrowth through interaction with neurexin-1? and activation of fibroblast growth factor receptor-1 Gjrlund MD , et al. (2012) No -
34 Support Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion Onat OE , et al. (2012) Yes -
35 Support Rate of de novo mutations and the importance of father's age to disease risk Kong A , et al. (2012) Yes -
36 Support 2p16.3 microdeletion with partial deletion of the neurexin-1 gene in a female with developmental delays, short stature, and a congenital diaphragmatic hernia Bermudez-Wagner K , et al. (2012) No -
37 Support A discovery resource of rare copy number variations in individuals with autism spectrum disorder Prasad A , et al. (2013) Yes -
38 Support Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy Mller RS , et al. (2013) No ID
39 Recent Recommendation Neurexin regulates visual function via mediating retinoid transport to promote rhodopsin maturation Tian Y , et al. (2013) No -
40 Support Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder Girirajan S , et al. (2013) Yes -
41 Support Investigation of NRXN1 deletions: clinical and molecular characterization Dabell MP , et al. (2013) No ASD, ADHD, Epilepsy
42 Support Identification of rare copy number variants in high burden schizophrenia families Van Den Bossche MJ , et al. (2013) No -
43 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
44 Support CNV analysis in Tourette syndrome implicates large genomic rearrangements in COL8A1 and NRXN1 Nag A , et al. (2013) No -
45 Recent Recommendation Functional impacts of NRXN1 knockdown on neurodevelopment in stem cell models Zeng L , et al. (2013) No -
46 Support Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing Jiang YH , et al. (2013) Yes -
47 Support Identification of candidate intergenic risk loci in autism spectrum disorder Walker S and Scherer SW (2013) Yes -
48 Support Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with autism spectrum disorder Koshimizu E , et al. (2013) Yes ID, epilepsy
49 Support A survey of rare coding variants in candidate genes in schizophrenia by deep sequencing Hu X , et al. (2013) No -
50 Support Etiological yield of SNP microarrays in idiopathic intellectual disability Utine GE , et al. (2014) No ASD or autistic features, epilepsy
51 Support Fraternal twins with autism, severe cognitive deficit, and epilepsy: diagnostic role of chromosomal microarray analysis Imitola J , et al. (2014) No ASD, ID, epilepsy
52 Support Refining analyses of copy number variation identifies specific genes associated with developmental delay Coe BP , et al. (2014) Yes -
53 Recent Recommendation Targeted combinatorial alternative splicing generates brain region-specific repertoires of neurexins Schreiner D , et al. (2014) No -
54 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
55 Support Recurrent de novo mutations implicate novel genes underlying simplex autism risk O'Roak BJ , et al. (2014) Yes -
56 Support A boy with dysmorphic features, intellectual disability, and biallelic homozygous deletion in NRXN1 Holmquist P (2014) No -
57 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No Hypotonia
58 Support A common cognitive, psychiatric, and dysmorphic phenotype in carriers of NRXN1 deletion Vias-Jornet M , et al. (2015) No ASD, BPD, ADHD
59 Recent Recommendation Neurexin 1 (NRXN1) splice isoform expression during human neocortical development and aging Jenkins AK , et al. (2015) No -
60 Support Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder Tammimies K , et al. (2015) Yes -
61 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
62 Support Frequency and Complexity of De Novo Structural Mutation in Autism Brandler WM , et al. (2016) Yes -
63 Recent Recommendation Molecular characterization of NRXN1 deletions from 19,263 clinical microarray cases identifies exons important for neurodevelopmental disease expression Lowther C , et al. (2016) Yes -
64 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
65 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies Redin C , et al. (2016) No -
66 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases Stessman HA , et al. (2017) Yes -
67 Support Mutation analysis of the NRXN1 gene in autism spectrum disorders Onay H , et al. (2017) Yes -
68 Recent Recommendation Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome Huang AY , et al. (2017) No -
69 Support Variable phenotype expression in a family segregating microdeletions of the NRXN1 and MBD5 autism spectrum disorder susceptibility genes Woodbury-Smith M , et al. (2017) Yes Macrocephaly
70 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
71 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
72 Recent Recommendation A Statistical Framework for Mapping Risk Genes from De Novo Mutations in Whole-Genome-Sequencing Studies Liu Y , et al. (2018) Yes -
73 Recent Recommendation NRXN1 deletion syndrome; phenotypic and penetrance data from 34 families Al Shehhi M , et al. (2018) No ASD, epilepsy/seizures
74 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
75 Support Both rare and common genetic variants contribute to autism in the Faroe Islands Leblond CS , et al. (2019) Yes -
76 Recent Recommendation Phenotypic spectrum of NRXN1 mono- and bi-allelic deficiency: A systematic review Castronovo P , et al. (2019) No -
77 Support Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with developmental disorders Schluth-Bolard C , et al. (2019) No Behavioral abnormalities
78 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population Monies D , et al. (2019) No Stereotypies
79 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
80 Support Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder Munnich A , et al. (2019) Yes -
81 Recent Recommendation Neuronal impact of patient-specific aberrant NRXN1? splicing Flaherty E , et al. (2019) No -
82 Support Increased Ca 2+ signaling in NRXN1? +/- neurons derived from ASD induced pluripotent stem cells Avazzadeh S , et al. (2020) Yes -
83 Support The clinical relevance of intragenic NRXN1 deletions Cosemans N , et al. (2020) No -
84 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
85 Support Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use Husson T , et al. (2020) Yes -
86 Support Further insight into the neurobehavioral pattern of children carrying the 2p16.3 heterozygous deletion involving NRXN1: Report of five new cases Alfieri P et al. (2020) Yes Epilepsy/seizures
87 Support Genome-wide detection of tandem DNA repeats that are expanded in autism Trost B et al. (2020) Yes -
88 Support Functional characterization of rare NRXN1 variants identified in autism spectrum disorders and schizophrenia Ishizuka K et al. (2020) Yes -
89 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes ID
90 Support - Cameli C et al. (2021) Yes DD
91 Support - Ohashi K et al. (2021) Yes -
92 Support - Taşkıran EZ et al. (2021) No ADHD
93 Support - Pak C et al. (2021) No -
94 Support - Kight KE et al. (2021) Yes -
95 Support - Liu Y et al. (2021) Yes -
96 Support - Avazzadeh S et al. (2021) Yes -
97 Support - Chen S et al. (2021) Yes Epilepsy/seizures
98 Support - Hughes RB et al. (2022) No -
99 Support - Levy KA et al. (2022) No -
100 Highly Cited Binding properties of neuroligin 1 and neurexin 1beta reveal function as heterophilic cell adhesion molecules Nguyen T and Sdhof TC (1997) No -
Rare Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
Common Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.999C>T;c.900C>T;c.840C>T;c.105C>T p.(=) synonymous_variant - - - 18179900 Kim HG , et al. (2008)
c.511C>T p.(=) synonymous_variant - - - 18179900 Kim HG , et al. (2008)
c.*110G>A - 3_prime_UTR_variant - - - 21687627 Voineskos AN , et al. (2011)
c.999C>T;c.900C>T;c.840C>T;c.105C>T p.(=) synonymous_variant - - - 22405623 Liu Y , et al. (2012)
SFARI Gene score
1

High Confidence

[

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.

Krishnan Probability Score

Score 0.93000000000001

Ranking 2/25841 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 0.9999487383563

Ranking 587/18225 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
Iossifov Probability Score

Score 0.946

Ranking 86/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 2.3114044581107E-7

Ranking 4/18665 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 132

Ranking 5/461 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 0.4059312435315

Ranking 1391/20870 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 NRXN1(1 CNVs)
2p16.3 73 Deletion-Duplication 113  /  517
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
Abpa2 amyloid beta (A4) precursor protein-binding, family A, member 2 Rat Protein Binding 83610 O35431
Chadl chondroadherin-like Mouse Protein Binding 214685 E9Q7T7
Lrrtm1 leucine rich repeat transmembrane neuronal 1 Mouse Protein Binding 74342 Q8K377
Nlgn4l neuroligin 4-like Mouse Protein Binding 100113365 B0F2B4
Nxph1 neurexophilin 1 Rat Protein Binding 25501 Q63366
Nxph3 neurexophilin 3 Rat Protein Binding 59315 Q9Z2N5
SDCBP2 syndecan binding protein (syntenin) 2 Human Protein Binding 27111 Q9H190
Spon1 spondin 1, (f-spondin) extracellular matrix protein Mouse Protein Binding 233744 Q8VCC9
Syt2 synaptotagmin II Rat Protein Binding 24805 P29101
Syt6 synaptotagmin VI Rat Protein Binding 60565 Q62746
Sytl1 synaptotagmin-like 1 Mouse Protein Binding 269589 Q99N80
Sytl2 synaptotagmin-like 2 Mouse Protein Binding 83671 Q99N50
Sytl3 synaptotagmin-like 3 Mouse Protein Binding 83672 Q99N48
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