Human Gene Module / Chromosome 2 / NRXN1

NRXN1neurexin 1

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
40 / 81
Rare Variants / Common Variants
164 / 4
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
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association
Chromosome Band
2p16.3
Associated Disorders
BPD, SCZ, EPS, ASD, ADHD, ID, EP
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.

Reports related to NRXN1 (81 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 D... 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 diaphragma... 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 aut... 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 expre... 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 develop... 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 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   (164)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss - - - 18945720 Rujescu D , et al. (2008)
- - copy_number_loss De novo - - 23533028 Bna F , et al. (2013)
- - copy_number_loss Unknown - - 23533028 Bna F , et al. (2013)
- - copy_number_loss Unknown - - 23533600 Nag A , et al. (2013)
- - missense_variant De novo - - 29754769 Liu Y , et al. (2018)
- - splicing_variant De novo - - 29754769 Liu Y , et al. (2018)
- - copy_number_gain - - - 18940311 Vrijenhoek T , et al. (2008)
- - copy_number_loss - - - 18940311 Vrijenhoek T , et al. (2008)
- - copy_number_gain De novo - - 27841880 Redin C , et al. (2016)
- - copy_number_loss De novo - - 18057082 Zahir FR , et al. (2007)
- - copy_number_loss De novo - - 21827697 Gregor A , et al. (2011)
- - copy_number_loss De novo - - 22617343 Schaaf CP , et al. (2012)
- - copy_number_loss Unknown - - 22617343 Schaaf CP , et al. (2012)
- - copy_number_loss De novo - - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Unknown - - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Unknown - - 31406558 Munnich A , et al. (2019)
- - copy_number_loss De novo - - 26325558 Tammimies K , et al. (2015)
- - copy_number_loss De novo - - 30031152 Al Shehhi M , et al. (2018)
- - copy_number_loss Unknown - - 30031152 Al Shehhi M , et al. (2018)
- - copy_number_loss De novo - Simplex 23533600 Nag A , et al. (2013)
- - loss_of_function_variant De novo - - 29754769 Liu Y , et al. (2018)
- - translocation De novo - - 30923172 Schluth-Bolard C , et al. (2019)
- - copy_number_loss Familial Maternal - 23533028 Bna F , et al. (2013)
- - copy_number_loss Familial Paternal - 23533028 Bna F , et al. (2013)
c.105C>A p.(=) synonymous_variant - - - 18179900 Kim HG , et al. (2008)
c.912C>T p.(=) synonymous_variant - - - 18179900 Kim HG , et al. (2008)
- - copy_number_gain De novo - Simplex 20531469 Pinto D , et al. (2010)
- - copy_number_loss De novo - Unknown 20531469 Pinto D , et al. (2010)
c.3165C>T p.(=) synonymous_variant - - - 18179900 Kim HG , et al. (2008)
c.3975C>T p.(=) synonymous_variant - - - 18179900 Kim HG , et al. (2008)
c.4374A>G p.(=) synonymous_variant - - - 18179900 Kim HG , et al. (2008)
- - copy_number_loss De novo - Simplex 20468056 Ching MS , et al. (2010)
- - copy_number_loss Unknown - Simplex 20468056 Ching MS , et al. (2010)
- - copy_number_loss Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_loss Apparently de novo - - 23533028 Bna F , et al. (2013)
c.41C>T p.Ser14Leu missense_variant - - - 17034946 Feng J , et al. (2006)
c.53T>A p.Leu18Gln missense_variant - - - 18179900 Kim HG , et al. (2008)
- - copy_number_loss Familial Maternal - 20531469 Pinto D , et al. (2010)
- - copy_number_loss Familial Paternal - 20531469 Pinto D , et al. (2010)
- - copy_number_loss Unknown Not maternal - 23533028 Bna F , et al. (2013)
- - copy_number_loss Familial Maternal - 21827697 Gregor A , et al. (2011)
- - copy_number_loss Familial Paternal - 21827697 Gregor A , et al. (2011)
- - copy_number_loss De novo - Multiplex 23294455 Mller RS , et al. (2013)
- - copy_number_loss De novo - Simplex 30675382 Leblond CS , et al. (2019)
- - copy_number_loss Familial Maternal - 22617343 Schaaf CP , et al. (2012)
- - copy_number_loss Familial Paternal - 22617343 Schaaf CP , et al. (2012)
- - copy_number_loss Familial Maternal - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Familial Paternal - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Familial Paternal - 31406558 Munnich A , et al. (2019)
- - copy_number_loss De novo - Multiplex 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Unknown - Multiplex 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Unknown - Multiplex 25149956 Imitola J , et al. (2014)
- - copy_number_loss De novo - Simplex 23375656 Girirajan S , et al. (2013)
c.81A>G p.(=) synonymous_variant Unknown - - 22405623 Liu Y , et al. (2012)
c.2242C>A p.Leu748Ile missense_variant - - - 18179900 Kim HG , et al. (2008)
- - copy_number_loss Inherited Maternal - 22617343 Schaaf CP , et al. (2012)
- - copy_number_loss Inherited Paternal - 22617343 Schaaf CP , et al. (2012)
c.132C>T p.(=) synonymous_variant Unknown - - 22405623 Liu Y , et al. (2012)
c.705C>G p.(=) synonymous_variant Unknown - - 22405623 Liu Y , et al. (2012)
c.337C>T p.Arg113Ter stop_gained De novo - - 22914163 Kong A , et al. (2012)
- - copy_number_loss Familial Maternal - 30031152 Al Shehhi M , et al. (2018)
- - copy_number_loss Familial Paternal - 30031152 Al Shehhi M , et al. (2018)
- - copy_number_loss De novo - Simplex 25614873 Vias-Jornet M , et al. (2015)
- - copy_number_loss Unknown Not maternal - 22617343 Schaaf CP , et al. (2012)
- - copy_number_loss Unknown - Simplex 23879678 Walker S and Scherer SW (2013)
- - copy_number_loss De novo - Multi-generational 23533600 Nag A , et al. (2013)
- - copy_number_loss Familial Maternal Simplex 19896112 Zweier C , et al. (2009)
- - copy_number_loss Familial Maternal Simplex 20468056 Ching MS , et al. (2010)
- - copy_number_loss Familial Paternal Simplex 20468056 Ching MS , et al. (2010)
- - 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 Paternal Simplex 23294455 Mller RS , et al. (2013)
C>A - stop_gained Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.607A>T p.Lys203Ter stop_gained Unknown - Unknown 24126932 Hu X , et al. (2013)
c.972C>G p.Tyr324Ter stop_gained Unknown - Unknown 24126932 Hu X , et al. (2013)
c.4205insACGG - frameshift_variant De novo - - 21424692 Gauthier J , et al. (2011)
c.1024+1G>A - splice_site_variant Unknown - Unknown 18490107 Yan J , et al. (2008)
- - copy_number_loss Unknown Not maternal Multiplex 23533028 Bna F , et al. (2013)
- - copy_number_loss Familial Paternal Multiplex 23294455 Mller RS , et al. (2013)
c.83G>C p.Gly28Ala missense_variant Unknown - - 22892527 Boccuto L , et al. (2012)
- - copy_number_loss Unknown Not maternal Simplex 20468056 Ching MS , et al. (2010)
- - copy_number_loss Familial Maternal Multiplex 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Familial Maternal Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss Familial Paternal Simplex 23375656 Girirajan S , et al. (2013)
del(AC) - frameshift_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.23G>C p.Arg8Pro missense_variant Unknown - Unknown 18490107 Yan J , et al. (2008)
- - copy_number_loss Inherited Maternal Multiplex 22617343 Schaaf CP , et al. (2012)
- - copy_number_loss Inherited Paternal Multiplex 22617343 Schaaf CP , et al. (2012)
- - copy_number_loss Familial Maternal Multiplex 21964664 Harrison V , et al. (2011)
- - copy_number_loss Familial Paternal Multiplex 21964664 Harrison V , et al. (2011)
c.-3G>T - 5_prime_UTR_variant Familial - - 22504536 Camacho-Garcia RJ , et al. (2012)
c.37C>T p.Leu13Phe missense_variant Unknown - Unknown 18490107 Yan J , et al. (2008)
c.83G>C p.Gly28Ala missense_variant Unknown - Unknown 18490107 Yan J , et al. (2008)
- - copy_number_loss Familial Maternal Multiplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss Familial Maternal Multiplex 27018473 Brandler WM , et al. (2016)
- - copy_number_gain Familial Paternal Simplex 23879678 Walker S and Scherer SW (2013)
- - copy_number_loss Familial Paternal Simplex 23879678 Walker S and Scherer SW (2013)
c.2110G>A p.Gly704Arg missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.1994C>T p.Thr665Ile missense_variant Unknown - Unknown 18490107 Yan J , et al. (2008)
c.2143G>A p.Glu715Lys missense_variant Unknown - Unknown 18490107 Yan J , et al. (2008)
- - copy_number_loss Familial Maternal Multi-generational 23533028 Bna F , et al. (2013)
- - copy_number_loss Familial Paternal Multi-generational 23533028 Bna F , et al. (2013)
- - copy_number_loss Familial Parental Multi-generational 23533600 Nag A , et al. (2013)
c.64G>C p.Gly22Arg missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.2865T>A p.Tyr955Ter stop_gained De novo - Simplex 22542183 Iossifov I , et al. (2012)
- - copy_number_loss Familial Maternal Multiplex 23879678 Walker S and Scherer SW (2013)
- - copy_number_loss Familial Paternal Simplex 28649445 Woodbury-Smith M , et al. (2017)
c.3333G>A p.Met1111Ile missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.844T>C p.Tyr282His missense_variant Familial Maternal - 22405623 Liu Y , et al. (2012)
- - copy_number_loss Familial Maternal or paternal Simplex 23533028 Bna F , et al. (2013)
- - copy_number_loss Familial Paternal or maternal Simplex 23533028 Bna F , et al. (2013)
c.2677C>G p.Leu893Val missense_variant Familial Paternal - 22405623 Liu Y , et al. (2012)
- - copy_number_loss Familial Maternal Multi-generational 22337556 Duong L , et al. (2012)
c.3403A>G p.Ile1135Val missense_variant Familial Paternal - 22405623 Liu Y , et al. (2012)
c.2573G>A p.Gly858Glu missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.2785G>A p.Asp929Asn missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.2785G>A p.Asp929Asn missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
- - copy_number_loss Familial Maternal Multi-generational 23294455 Mller RS , et al. (2013)
c.3308C>T p.Pro1103Leu missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.2558G>A p.Arg853His missense_variant De novo - Simplex 25418537 O'Roak BJ , et al. (2014)
- - copy_number_loss Familial Maternal Multiplex 23505263 Van Den Bossche MJ , et al. (2013)
c.455G>A p.Gly152Asp missense_variant Unknown - Unknown 24066114 Koshimizu E , et al. (2013)
c.302C>T p.Thr101Met missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.859A>C p.Lys287Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1174A>C p.Asn392His missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.2166G>T p.Gln722His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2725C>A p.Leu909Met missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2804T>G p.Leu935Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2884C>G p.Gln962Glu missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
- - copy_number_loss Familial Maternal Extended multiplex 30031152 Al Shehhi M , et al. (2018)
- - copy_number_loss Familial Maternal Multi-generational 30031152 Al Shehhi M , et al. (2018)
- - copy_number_loss Familial Paternal Multi-generational 30031152 Al Shehhi M , et al. (2018)
c.3G>T p.Met1? initiator_codon_variant Familial - - 22504536 Camacho-Garcia RJ , et al. (2012)
- - copy_number_loss;copy_number_loss Familial Both parents Simplex 25486015 Holmquist P (2014)
c.41C>T p.Ser14Leu missense_variant Familial Paternal Simplex 28289584 Onay H , et al. (2017)
c.2936C>G p.Ser979Ter stop_gained Familial Paternal Simplex 19896112 Zweier C , et al. (2009)
c.3763G>A p.Val1255Ile missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
- - copy_number_loss 4 de novo, 8 inherited, 18 unknown - Unknown 25217958 Coe BP , et al. (2014)
c.118A>T p.Thr40Ser missense_variant Familial Maternal Simplex 17034946 Feng J , et al. (2006)
ins(ACGG) p.Gly1402AspfsTer29 frameshift_variant De novo - - 20797689 Awadalla P , et al. (2010)
- - copy_number_loss Familial Maternal Multi-generational 25614873 Vias-Jornet M , et al. (2015)
c.2354G>A p.Arg785Gln missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
- - copy_number_loss Familial Maternal Possibly multi-generational 23533028 Bna F , et al. (2013)
- - copy_number_loss Familial Paternal Possibly multi-generational 23533028 Bna F , et al. (2013)
c.41C>T p.Ser14Leu missense_variant Familial Paternal Multiplex 17034946 Feng J , et al. (2006)
- - copy_number_gain Unknown Not maternal Simplex 20162629 Winiowiecka-Kowalnik B , et al. (2010)
- - copy_number_loss De novo - Multiplex 17322880 Autism Genome Project Consortium , et al. (2007)
- - copy_number_loss Familial Paternal Multi-generational 23207424 Bermudez-Wagner K , et al. (2012)
c.3018del p.Phe1006LeufsTer26 frameshift_variant Familial Maternal - 27824329 Wang T , et al. (2016)
- - copy_number_loss;copy_number_loss Familial Both parents Simplex 24508361 Utine GE , et al. (2014)
c.2653C>T p.His885Tyr missense_variant Familial Paternal Multiplex 23849776 Jiang YH , et al. (2013)
c.308C>T p.Thr103Ile missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
- - complex_structural_alteration Familial Paternal Multi-generational 27841880 Redin C , et al. (2016)
c.1945C>T p.Arg649Trp missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2880-1G>A - splice_site_variant Familial Paternal Multi-generational 22337556 Duong L , et al. (2012)
c.1691A>G p.Arg564Gly missense_variant Familial Paternal Multiplex 25363760 De Rubeis S , et al. (2014)
- - copy_number_loss Familial Maternal Multi-generational 20162629 Winiowiecka-Kowalnik B , et al. (2010)
c.2242C>A p.Leu748Ile missense_variant Familial Paternal Multi-generational 28289584 Onay H , et al. (2017)
c.1132G>A p.Gly378Ser missense_variant Familial Maternal Simplex 22504536 Camacho-Garcia RJ , et al. (2012)
c.1124G>A p.Arg375Gln missense_variant Familial Maternal Multiplex 22504536 Camacho-Garcia RJ , et al. (2012)
- - copy_number_gain Familial Maternal Possibly multi-generational 20162629 Winiowiecka-Kowalnik B , et al. (2010)
c.4166_4167delCCinsC p.Cys1390ValfsTer23 frameshift_variant De novo - Simplex 28191889 Stessman HA , et al. (2017)
c.[28G>A];[28G>A] p.[Gly10Ser];[Gly10Ser] missense_variant;missense_variant - - Multiplex 31130284 Monies D , et al. (2019)
c.2437C>T p.Arg813Cys missense_variant Familial Paternal Multi-generational 25533962 Deciphering Developmental Disorders Study (2014)
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

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). Integrated Transmission and De Novo Association (TADA) analysis of small de novo deletions and exome mutations from the Simons Simplex Collection, the Autism Sequencing Consortium, and the Autism Genome Project identified NRXN1 as a ASD risk gene with a false discovery rate (FDR) 0.01 (Sanders et al., 2015). Biallelic mutations in NRXN1 have also been implicated in Pitt-Hopkins-like syndrome 2, an autosomal recessive intellectual disability syndrome in which a significant number of affected individuals present with autistic features and/or motor stereotypies (Zweier et al., 2009; Harrison et al., 2011; Castronovo et al., 2019). 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).

Score Delta: Score remained at 2

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.

7/1/2019
2
icon
2

Score remained at 2

Description

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). Integrated Transmission and De Novo Association (TADA) analysis of small de novo deletions and exome mutations from the Simons Simplex Collection, the Autism Sequencing Consortium, and the Autism Genome Project identified NRXN1 as a ASD risk gene with a false discovery rate (FDR) 0.01 (Sanders et al., 2015). Biallelic mutations in NRXN1 have also been implicated in Pitt-Hopkins-like syndrome 2, an autosomal recessive intellectual disability syndrome in which a significant number of affected individuals present with autistic features and/or motor stereotypies (Zweier et al., 2009; Harrison et al., 2011; Castronovo et al., 2019). 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).

1/1/2019
2
icon
2

Score remained at 2

Description

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).

10/1/2018
2
icon
2

Score remained at 2

Description

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).

7/1/2018
2.1
icon
2

Score remained at 2

Description

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).

10/1/2017
2
icon
2

Score remained at 2

Description

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).

7/1/2017
2
icon
2

Score remained at 2

Description

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).

4/1/2017
2
icon
2

Score remained at 2

Description

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). 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).

Reports Added
[High frequency of neurexin 1beta signal peptide structural variants in patients with autism.2006] [Mapping autism risk loci using genetic linkage and chromosomal rearrangements.2007] [Disruption of neurexin 1 associated with autism spectrum disorder.2008] [Neurexin 1alpha structural variants associated with autism.2008] [Mouse neurexin-1alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments.2009] [Intragenic rearrangements in NRXN1 in three families with autism spectrum disorder, developmental delay, and speech delay.2010] [Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders.2010] [Functional impact of global rare copy number variation in autism spectrum disorders.2010] [Neurexin-1 and frontal lobe white matter: an overlapping intermediate phenotype for schizophrenia and autism spectrum disorders.2011] [De novo gene disruptions in children on the autistic spectrum.2012] [Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion.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] [Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.2013] [Identification of candidate intergenic risk loci in autism spectrum disorder.2013] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Refining analyses of copy number variation identifies specific genes associated with developmental delay.2014] [Phenotypic spectrum and genotype-phenotype correlations of NRXN1 exon deletions.2012] [Rate of de novo mutations and the importance of father's age to disease risk.2012] [Mutations in NRXN1 in a family multiply affected with brain disorders: NRXN1 mutations and brain disorders.2012] [Mutation analysis of the NRXN1 gene in a Chinese autism cohort.2012] [Mutations affecting synaptic levels of neurexin-1 in autism and mental retardation.2012] [2p16.3 microdeletion with partial deletion of the neurexin-1 gene in a female with developmental delays, short stature, and a congenital diaphragma...2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Investigation of NRXN1 deletions: clinical and molecular characterization.2013] [Etiological yield of SNP microarrays in idiopathic intellectual disability.2014] [Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy.2013] [Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1.2011] [A boy with dysmorphic features, intellectual disability, and biallelic homozygous deletion in NRXN1.2014] [A common cognitive, psychiatric, and dysmorphic phenotype in carriers of NRXN1 deletion.2015] [Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature.2013] [A patient with vertebral, cognitive and behavioural abnormalities and a de novo deletion of NRXN1alpha.2007] [CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in D...2009] [Compound heterozygous deletion of NRXN1 causing severe developmental delay with early onset epilepsy in two sisters.2011] [CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in D...2009] [Fraternal twins with autism, severe cognitive deficit, and epilepsy: diagnostic role of chromosomal microarray analysis.2014] [Recurrent CNVs disrupt three candidate genes in schizophrenia patients.2008] [Disruption of the neurexin 1 gene is associated with schizophrenia.2008] [Direct measure of the de novo mutation rate in autism and schizophrenia cohorts.2010] [Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia.2011] [Identification of rare copy number variants in high burden schizophrenia families.2013] [A survey of rare coding variants in candidate genes in schizophrenia by deep sequencing.2013] [CNV analysis in Tourette syndrome implicates large genomic rearrangements in COL8A1 and NRXN1.2013] [Binding properties of neuroligin 1 and neurexin 1beta reveal function as heterophilic cell adhesion molecules.1997] [Neurexin mediates the assembly of presynaptic terminals.2003] [Alternative splicing controls selective trans-synaptic interactions of the neuroligin-neurexin complex.2006] [Retrograde modulation of presynaptic release probability through signaling mediated by PSD-95-neuroligin.2007] [Silencing of neuroligin function by postsynaptic neurexins.2007] [Presynaptic targeting of alpha4beta 2 nicotinic acetylcholine receptors is regulated by neurexin-1beta.2009] [Sensory regulation of neuroligins and neurexin I in the honeybee brain.2010] [Neurexins physically and functionally interact with GABA(A) receptors.2010] [Trans-synaptic interaction of GluRdelta2 and Neurexin through Cbln1 mediates synapse formation in the cerebellum.2010] [Splice form dependence of beta-neurexin/neuroligin binding interactions.2010] [Modeling the functional genomics of autism using human neurons.2011] [Neuroligin-1 induces neurite outgrowth through interaction with neurexin-1 and activation of fibroblast growth factor receptor-1.2012] [Neurexin regulates visual function via mediating retinoid transport to promote rhodopsin maturation.2013] [Functional impacts of NRXN1 knockdown on neurodevelopment in stem cell models.2013] [Targeted combinatorial alternative splicing generates brain region-specific repertoires of neurexins.2014] [Neurexin 1 (NRXN1) splice isoform expression during human neocortical development and aging.2015] [Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Frequency and Complexity of De Novo Structural Mutation in Autism.2016] [Molecular characterization of NRXN1 deletions from 19,263 clinical microarray cases identifies exons important for neurodevelopmental disease expre...2016] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016] [Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017] [Mutation analysis of the NRXN1 gene in autism spectrum disorders.2017]
1/1/2017
2
icon
2

Score remained at 2

Description

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). 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).

10/1/2016
2
icon
2

Score remained at 2

Description

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). 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).

4/1/2016
2
icon
2

Score remained at 2

Description

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). 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).

Reports Added
[High frequency of neurexin 1beta signal peptide structural variants in patients with autism.2006] [Mapping autism risk loci using genetic linkage and chromosomal rearrangements.2007] [Disruption of neurexin 1 associated with autism spectrum disorder.2008] [Neurexin 1alpha structural variants associated with autism.2008] [Mouse neurexin-1alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments.2009] [Intragenic rearrangements in NRXN1 in three families with autism spectrum disorder, developmental delay, and speech delay.2010] [Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders.2010] [Functional impact of global rare copy number variation in autism spectrum disorders.2010] [Neurexin-1 and frontal lobe white matter: an overlapping intermediate phenotype for schizophrenia and autism spectrum disorders.2011] [De novo gene disruptions in children on the autistic spectrum.2012] [Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion.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] [Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.2013] [Identification of candidate intergenic risk loci in autism spectrum disorder.2013] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Refining analyses of copy number variation identifies specific genes associated with developmental delay.2014] [Phenotypic spectrum and genotype-phenotype correlations of NRXN1 exon deletions.2012] [Rate of de novo mutations and the importance of father's age to disease risk.2012] [Mutations in NRXN1 in a family multiply affected with brain disorders: NRXN1 mutations and brain disorders.2012] [Mutation analysis of the NRXN1 gene in a Chinese autism cohort.2012] [Mutations affecting synaptic levels of neurexin-1 in autism and mental retardation.2012] [2p16.3 microdeletion with partial deletion of the neurexin-1 gene in a female with developmental delays, short stature, and a congenital diaphragma...2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Investigation of NRXN1 deletions: clinical and molecular characterization.2013] [Etiological yield of SNP microarrays in idiopathic intellectual disability.2014] [Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy.2013] [Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1.2011] [A boy with dysmorphic features, intellectual disability, and biallelic homozygous deletion in NRXN1.2014] [A common cognitive, psychiatric, and dysmorphic phenotype in carriers of NRXN1 deletion.2015] [Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature.2013] [A patient with vertebral, cognitive and behavioural abnormalities and a de novo deletion of NRXN1alpha.2007] [CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in D...2009] [Compound heterozygous deletion of NRXN1 causing severe developmental delay with early onset epilepsy in two sisters.2011] [CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in D...2009] [Fraternal twins with autism, severe cognitive deficit, and epilepsy: diagnostic role of chromosomal microarray analysis.2014] [Recurrent CNVs disrupt three candidate genes in schizophrenia patients.2008] [Disruption of the neurexin 1 gene is associated with schizophrenia.2008] [Direct measure of the de novo mutation rate in autism and schizophrenia cohorts.2010] [Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia.2011] [Identification of rare copy number variants in high burden schizophrenia families.2013] [A survey of rare coding variants in candidate genes in schizophrenia by deep sequencing.2013] [CNV analysis in Tourette syndrome implicates large genomic rearrangements in COL8A1 and NRXN1.2013] [Binding properties of neuroligin 1 and neurexin 1beta reveal function as heterophilic cell adhesion molecules.1997] [Neurexin mediates the assembly of presynaptic terminals.2003] [Alternative splicing controls selective trans-synaptic interactions of the neuroligin-neurexin complex.2006] [Retrograde modulation of presynaptic release probability through signaling mediated by PSD-95-neuroligin.2007] [Silencing of neuroligin function by postsynaptic neurexins.2007] [Presynaptic targeting of alpha4beta 2 nicotinic acetylcholine receptors is regulated by neurexin-1beta.2009] [Sensory regulation of neuroligins and neurexin I in the honeybee brain.2010] [Neurexins physically and functionally interact with GABA(A) receptors.2010] [Trans-synaptic interaction of GluRdelta2 and Neurexin through Cbln1 mediates synapse formation in the cerebellum.2010] [Splice form dependence of beta-neurexin/neuroligin binding interactions.2010] [Modeling the functional genomics of autism using human neurons.2011] [Neuroligin-1 induces neurite outgrowth through interaction with neurexin-1 and activation of fibroblast growth factor receptor-1.2012] [Neurexin regulates visual function via mediating retinoid transport to promote rhodopsin maturation.2013] [Functional impacts of NRXN1 knockdown on neurodevelopment in stem cell models.2013] [Targeted combinatorial alternative splicing generates brain region-specific repertoires of neurexins.2014] [Neurexin 1 (NRXN1) splice isoform expression during human neocortical development and aging.2015] [Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Frequency and Complexity of De Novo Structural Mutation in Autism.2016] [Molecular characterization of NRXN1 deletions from 19,263 clinical microarray cases identifies exons important for neurodevelopmental disease expre...2016]
1/1/2016
2
icon
2

Score remained at 2

Description

Ching et al. provide results that approach genome-wide significant criteria (8 x 10-7), with 12/3450 cases observed to carry deletions as compared to 0 controls obtained from other work. A similar range of outcomes is observed amongst cases including autism spectrum disorders, mental retardation, language delays, and hypotonia. The sample overlap with Bucan et al. is unclear, but similar results are reported, with exonic deletions in 9 of ~2000 cases versus 0 / ~ 2500 controls. Zweier et al. show that an individual with autosomal-recessive Pitt-Hopkins-like mental retardation is a carrier for two heterozygous variants argued to be pathogenic.

Reports Added
[High frequency of neurexin 1beta signal peptide structural variants in patients with autism.2006] [Mapping autism risk loci using genetic linkage and chromosomal rearrangements.2007] [Disruption of neurexin 1 associated with autism spectrum disorder.2008] [Neurexin 1alpha structural variants associated with autism.2008] [Mouse neurexin-1alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments.2009] [Intragenic rearrangements in NRXN1 in three families with autism spectrum disorder, developmental delay, and speech delay.2010] [Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders.2010] [Functional impact of global rare copy number variation in autism spectrum disorders.2010] [Neurexin-1 and frontal lobe white matter: an overlapping intermediate phenotype for schizophrenia and autism spectrum disorders.2011] [De novo gene disruptions in children on the autistic spectrum.2012] [Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion.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] [Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.2013] [Identification of candidate intergenic risk loci in autism spectrum disorder.2013] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Refining analyses of copy number variation identifies specific genes associated with developmental delay.2014] [Phenotypic spectrum and genotype-phenotype correlations of NRXN1 exon deletions.2012] [Rate of de novo mutations and the importance of father's age to disease risk.2012] [Mutations in NRXN1 in a family multiply affected with brain disorders: NRXN1 mutations and brain disorders.2012] [Mutation analysis of the NRXN1 gene in a Chinese autism cohort.2012] [Mutations affecting synaptic levels of neurexin-1 in autism and mental retardation.2012] [2p16.3 microdeletion with partial deletion of the neurexin-1 gene in a female with developmental delays, short stature, and a congenital diaphragma...2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Investigation of NRXN1 deletions: clinical and molecular characterization.2013] [Etiological yield of SNP microarrays in idiopathic intellectual disability.2014] [Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy.2013] [Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1.2011] [A boy with dysmorphic features, intellectual disability, and biallelic homozygous deletion in NRXN1.2014] [A common cognitive, psychiatric, and dysmorphic phenotype in carriers of NRXN1 deletion.2015] [Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature.2013] [A patient with vertebral, cognitive and behavioural abnormalities and a de novo deletion of NRXN1alpha.2007] [CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in D...2009] [Compound heterozygous deletion of NRXN1 causing severe developmental delay with early onset epilepsy in two sisters.2011] [CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in D...2009] [Fraternal twins with autism, severe cognitive deficit, and epilepsy: diagnostic role of chromosomal microarray analysis.2014] [Recurrent CNVs disrupt three candidate genes in schizophrenia patients.2008] [Disruption of the neurexin 1 gene is associated with schizophrenia.2008] [Direct measure of the de novo mutation rate in autism and schizophrenia cohorts.2010] [Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia.2011] [Identification of rare copy number variants in high burden schizophrenia families.2013] [A survey of rare coding variants in candidate genes in schizophrenia by deep sequencing.2013] [CNV analysis in Tourette syndrome implicates large genomic rearrangements in COL8A1 and NRXN1.2013] [Binding properties of neuroligin 1 and neurexin 1beta reveal function as heterophilic cell adhesion molecules.1997] [Neurexin mediates the assembly of presynaptic terminals.2003] [Alternative splicing controls selective trans-synaptic interactions of the neuroligin-neurexin complex.2006] [Retrograde modulation of presynaptic release probability through signaling mediated by PSD-95-neuroligin.2007] [Silencing of neuroligin function by postsynaptic neurexins.2007] [Presynaptic targeting of alpha4beta 2 nicotinic acetylcholine receptors is regulated by neurexin-1beta.2009] [Sensory regulation of neuroligins and neurexin I in the honeybee brain.2010] [Neurexins physically and functionally interact with GABA(A) receptors.2010] [Trans-synaptic interaction of GluRdelta2 and Neurexin through Cbln1 mediates synapse formation in the cerebellum.2010] [Splice form dependence of beta-neurexin/neuroligin binding interactions.2010] [Modeling the functional genomics of autism using human neurons.2011] [Neuroligin-1 induces neurite outgrowth through interaction with neurexin-1 and activation of fibroblast growth factor receptor-1.2012] [Neurexin regulates visual function via mediating retinoid transport to promote rhodopsin maturation.2013] [Functional impacts of NRXN1 knockdown on neurodevelopment in stem cell models.2013] [Targeted combinatorial alternative splicing generates brain region-specific repertoires of neurexins.2014] [Neurexin 1 (NRXN1) splice isoform expression during human neocortical development and aging.2015] [Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
7/1/2015
2
icon
2

Score remained at 2

Description

Ching et al. provide results that approach genome-wide significant criteria (8 x 10-7), with 12/3450 cases observed to carry deletions as compared to 0 controls obtained from other work. A similar range of outcomes is observed amongst cases including autism spectrum disorders, mental retardation, language delays, and hypotonia. The sample overlap with Bucan et al. is unclear, but similar results are reported, with exonic deletions in 9 of ~2000 cases versus 0 / ~ 2500 controls. Zweier et al. show that an individual with autosomal-recessive Pitt-Hopkins-like mental retardation is a carrier for two heterozygous variants argued to be pathogenic.

Reports Added
[High frequency of neurexin 1beta signal peptide structural variants in patients with autism.2006] [Mapping autism risk loci using genetic linkage and chromosomal rearrangements.2007] [Disruption of neurexin 1 associated with autism spectrum disorder.2008] [Neurexin 1alpha structural variants associated with autism.2008] [Mouse neurexin-1alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments.2009] [Intragenic rearrangements in NRXN1 in three families with autism spectrum disorder, developmental delay, and speech delay.2010] [Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders.2010] [Functional impact of global rare copy number variation in autism spectrum disorders.2010] [Neurexin-1 and frontal lobe white matter: an overlapping intermediate phenotype for schizophrenia and autism spectrum disorders.2011] [De novo gene disruptions in children on the autistic spectrum.2012] [Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion.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] [Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.2013] [Identification of candidate intergenic risk loci in autism spectrum disorder.2013] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Refining analyses of copy number variation identifies specific genes associated with developmental delay.2014] [Phenotypic spectrum and genotype-phenotype correlations of NRXN1 exon deletions.2012] [Rate of de novo mutations and the importance of father's age to disease risk.2012] [Mutations in NRXN1 in a family multiply affected with brain disorders: NRXN1 mutations and brain disorders.2012] [Mutation analysis of the NRXN1 gene in a Chinese autism cohort.2012] [Mutations affecting synaptic levels of neurexin-1 in autism and mental retardation.2012] [2p16.3 microdeletion with partial deletion of the neurexin-1 gene in a female with developmental delays, short stature, and a congenital diaphragma...2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Investigation of NRXN1 deletions: clinical and molecular characterization.2013] [Etiological yield of SNP microarrays in idiopathic intellectual disability.2014] [Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy.2013] [Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1.2011] [A boy with dysmorphic features, intellectual disability, and biallelic homozygous deletion in NRXN1.2014] [A common cognitive, psychiatric, and dysmorphic phenotype in carriers of NRXN1 deletion.2015] [Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature.2013] [A patient with vertebral, cognitive and behavioural abnormalities and a de novo deletion of NRXN1alpha.2007] [CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in D...2009] [Compound heterozygous deletion of NRXN1 causing severe developmental delay with early onset epilepsy in two sisters.2011] [CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in D...2009] [Fraternal twins with autism, severe cognitive deficit, and epilepsy: diagnostic role of chromosomal microarray analysis.2014] [Recurrent CNVs disrupt three candidate genes in schizophrenia patients.2008] [Disruption of the neurexin 1 gene is associated with schizophrenia.2008] [Direct measure of the de novo mutation rate in autism and schizophrenia cohorts.2010] [Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia.2011] [Identification of rare copy number variants in high burden schizophrenia families.2013] [A survey of rare coding variants in candidate genes in schizophrenia by deep sequencing.2013] [CNV analysis in Tourette syndrome implicates large genomic rearrangements in COL8A1 and NRXN1.2013] [Binding properties of neuroligin 1 and neurexin 1beta reveal function as heterophilic cell adhesion molecules.1997] [Neurexin mediates the assembly of presynaptic terminals.2003] [Alternative splicing controls selective trans-synaptic interactions of the neuroligin-neurexin complex.2006] [Retrograde modulation of presynaptic release probability through signaling mediated by PSD-95-neuroligin.2007] [Silencing of neuroligin function by postsynaptic neurexins.2007] [Presynaptic targeting of alpha4beta 2 nicotinic acetylcholine receptors is regulated by neurexin-1beta.2009] [Sensory regulation of neuroligins and neurexin I in the honeybee brain.2010] [Neurexins physically and functionally interact with GABA(A) receptors.2010] [Trans-synaptic interaction of GluRdelta2 and Neurexin through Cbln1 mediates synapse formation in the cerebellum.2010] [Splice form dependence of beta-neurexin/neuroligin binding interactions.2010] [Modeling the functional genomics of autism using human neurons.2011] [Neuroligin-1 induces neurite outgrowth through interaction with neurexin-1 and activation of fibroblast growth factor receptor-1.2012] [Neurexin regulates visual function via mediating retinoid transport to promote rhodopsin maturation.2013] [Functional impacts of NRXN1 knockdown on neurodevelopment in stem cell models.2013] [Targeted combinatorial alternative splicing generates brain region-specific repertoires of neurexins.2014] [Neurexin 1 (NRXN1) splice isoform expression during human neocortical development and aging.2015] [Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.2015]
1/1/2015
2
icon
2

Score remained at 2

Description

Ching et al. provide results that approach genome-wide significant criteria (8 x 10-7), with 12/3450 cases observed to carry deletions as compared to 0 controls obtained from other work. A similar range of outcomes is observed amongst cases including autism spectrum disorders, mental retardation, language delays, and hypotonia. The sample overlap with Bucan et al. is unclear, but similar results are reported, with exonic deletions in 9 of ~2000 cases versus 0 / ~ 2500 controls. Zweier et al. show that an individual with autosomal-recessive Pitt-Hopkins-like mental retardation is a carrier for two heterozygous variants argued to be pathogenic.

10/1/2014
2
icon
2

Score remained at 2

Description

Ching et al. provide results that approach genome-wide significant criteria (8 x 10-7), with 12/3450 cases observed to carry deletions as compared to 0 controls obtained from other work. A similar range of outcomes is observed amongst cases including autism spectrum disorders, mental retardation, language delays, and hypotonia. The sample overlap with Bucan et al. is unclear, but similar results are reported, with exonic deletions in 9 of ~2000 cases versus 0 / ~ 2500 controls. Zweier et al. show that an individual with autosomal-recessive Pitt-Hopkins-like mental retardation is a carrier for two heterozygous variants argued to be pathogenic.

7/1/2014
No data
icon
2

Increased from No data to 2

Description

Ching et al. provide results that approach genome-wide significant criteria (8 x 10-7), with 12/3450 cases observed to carry deletions as compared to 0 controls obtained from other work. A similar range of outcomes is observed amongst cases including autism spectrum disorders, mental retardation, language delays, and hypotonia. The sample overlap with Bucan et al. is unclear, but similar results are reported, with exonic deletions in 9 of ~2000 cases versus 0 / ~ 2500 controls. Zweier et al. show that an individual with autosomal-recessive Pitt-Hopkins-like mental retardation is a carrier for two heterozygous variants argued to be pathogenic.

Reports Added
[Binding properties of neuroligin 1 and neurexin 1beta reveal function as heterophilic cell adhesion molecules.1997] [Neurexin mediates the assembly of presynaptic terminals.2003] [Alternative splicing controls selective trans-synaptic interactions of the neuroligin-neurexin complex.2006] [High frequency of neurexin 1beta signal peptide structural variants in patients with autism.2006] [Retrograde modulation of presynaptic release probability through signaling mediated by PSD-95-neuroligin.2007] [Mapping autism risk loci using genetic linkage and chromosomal rearrangements.2007] [Silencing of neuroligin function by postsynaptic neurexins.2007] [A patient with vertebral, cognitive and behavioural abnormalities and a de novo deletion of NRXN1alpha.2007] [Disruption of neurexin 1 associated with autism spectrum disorder.2008] [Neurexin 1alpha structural variants associated with autism.2008] [Recurrent CNVs disrupt three candidate genes in schizophrenia patients.2008] [Disruption of the neurexin 1 gene is associated with schizophrenia.2008] [Presynaptic targeting of alpha4beta 2 nicotinic acetylcholine receptors is regulated by neurexin-1beta.2009] [Mouse neurexin-1alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments.2009] [CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in D...2009] [CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in D...2009] [Sensory regulation of neuroligins and neurexin I in the honeybee brain.2010] [Intragenic rearrangements in NRXN1 in three families with autism spectrum disorder, developmental delay, and speech delay.2010] [Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders.2010] [Neurexins physically and functionally interact with GABA(A) receptors.2010] [Functional impact of global rare copy number variation in autism spectrum disorders.2010] [Trans-synaptic interaction of GluRdelta2 and Neurexin through Cbln1 mediates synapse formation in the cerebellum.2010] [Splice form dependence of beta-neurexin/neuroligin binding interactions.2010] [Direct measure of the de novo mutation rate in autism and schizophrenia cohorts.2010] [Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia.2011] [Modeling the functional genomics of autism using human neurons.2011] [Neurexin-1 and frontal lobe white matter: an overlapping intermediate phenotype for schizophrenia and autism spectrum disorders.2011] [Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1.2011] [Compound heterozygous deletion of NRXN1 causing severe developmental delay with early onset epilepsy in two sisters.2011] [Mutations in NRXN1 in a family multiply affected with brain disorders: NRXN1 mutations and brain disorders.2012] [Mutation analysis of the NRXN1 gene in a Chinese autism cohort.2012] [Mutations affecting synaptic levels of neurexin-1 in autism and mental retardation.2012] [De novo gene disruptions in children on the autistic spectrum.2012] [Phenotypic spectrum and genotype-phenotype correlations of NRXN1 exon deletions.2012] [Neuroligin-1 induces neurite outgrowth through interaction with neurexin-1 and activation of fibroblast growth factor receptor-1.2012] [Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion.2012] [Rate of de novo mutations and the importance of father's age to disease risk.2012] [2p16.3 microdeletion with partial deletion of the neurexin-1 gene in a female with developmental delays, short stature, and a congenital diaphragma...2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy.2013] [Neurexin regulates visual function via mediating retinoid transport to promote rhodopsin maturation.2013] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Investigation of NRXN1 deletions: clinical and molecular characterization.2013] [Identification of rare copy number variants in high burden schizophrenia families.2013] [Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature.2013] [CNV analysis in Tourette syndrome implicates large genomic rearrangements in COL8A1 and NRXN1.2013] [Functional impacts of NRXN1 knockdown on neurodevelopment in stem cell models.2013] [Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.2013] [Identification of candidate intergenic risk loci in autism spectrum disorder.2013] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [A survey of rare coding variants in candidate genes in schizophrenia by deep sequencing.2013] [Etiological yield of SNP microarrays in idiopathic intellectual disability.2014] [Fraternal twins with autism, severe cognitive deficit, and epilepsy: diagnostic role of chromosomal microarray analysis.2014]
4/1/2014
No data
icon
2

Increased from No data to 2

Description

Ching et al. provide results that approach genome-wide significant criteria (8 x 10-7), with 12/3450 cases observed to carry deletions as compared to 0 controls obtained from other work. A similar range of outcomes is observed amongst cases including autism spectrum disorders, mental retardation, language delays, and hypotonia. The sample overlap with Bucan et al. is unclear, but similar results are reported, with exonic deletions in 9 of ~2000 cases versus 0 / ~ 2500 controls. Zweier et al. show that an individual with autosomal-recessive Pitt-Hopkins-like mental retardation is a carrier for two heterozygous variants argued to be pathogenic.

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 63 Deletion-Duplication 102  /  483
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
Submit New Gene

Report an Error