Human Gene Module / Chromosome 2 / NRXN1

NRXN1neurexin 1

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
35 / 72
Rare Variants / Common Variants
245 / 4
Aliases
NRXN1, DKFZp313P2036,  FLJ35941,  Hs.22998,  KIAA0578,  PTHSL2
Associated Syndromes
Pitt-Hopkins-like syndrome 2, Tourette syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association
Chromosome Band
2p16.3
Associated Disorders
BPD, ASD, EPS, ID, ADHD, SCZ, 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 (72 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 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 MR
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 A boy with dysmorphic features, intellectual disability, and biallelic homozygous deletion in NRXN1. Holmquist P (2014) No -
56 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No Hypotonia
57 Support A common cognitive, psychiatric, and dysmorphic phenotype in carriers of NRXN1 deletion. Vias-Jornet M , et al. (2015) No ASD, BPD, ADHD
58 Recent recommendation Neurexin 1 (NRXN1) splice isoform expression during human neocortical development and aging. Jenkins AK , et al. (2015) No -
59 Support Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder. Tammimies K , et al. (2015) Yes -
60 Recent recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
61 Support Frequency and Complexity of De Novo Structural Mutation in Autism. Brandler WM , et al. (2016) Yes -
62 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 -
63 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
64 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies. Redin C , et al. (2016) No -
65 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Stessman HA , et al. (2017) Yes -
66 Support Mutation analysis of the NRXN1 gene in autism spectrum disorders. Onay H , et al. (2017) Yes -
67 Recent recommendation Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome. Huang AY , et al. (2017) No -
68 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
69 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders. Li J , et al. (2017) Yes -
70 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder. Takata A , et al. (2018) Yes -
71 Recent recommendation A Statistical Framework for Mapping Risk Genes from De Novo Mutations in Whole-Genome-Sequencing Studies. Liu Y , et al. (2018) Yes -
72 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   (245)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.41C>T p.Ser14Leu missense_variant Familial Paternal Multiplex 17034946 Feng J , et al. (2006)
c.41C>T p.Ser14Leu missense_variant - - - 17034946 Feng J , et al. (2006)
c.118A>T p.Thr40Ser missense_variant Familial Maternal Simplex 17034946 Feng J , et al. (2006)
- - copy_number_loss De novo - Multiplex 17322880 Autism Genome Project Consortium , et al. (2007)
- - copy_number_loss De novo - - 18057082 Zahir FR , et al. (2007)
c.53T>A p.Leu18Gln missense_variant - - - 18179900 Kim HG , et al. (2008)
c.105C>A p.(=) synonymous_variant - - - 18179900 Kim HG , et al. (2008)
c.912C>T p.(=) synonymous_variant - - - 18179900 Kim HG , et al. (2008)
c.2242C>A p.Leu748Ile missense_variant - - - 18179900 Kim HG , et al. (2008)
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)
c.23G>C p.Arg8Pro missense_variant Unknown - Unknown 18490107 Yan J , et al. (2008)
c.37C>T p.Leu13Phe missense_variant Unknown - Unknown 18490107 Yan J , et al. (2008)
c.1024+1G>A - splice_site_variant Unknown - Unknown 18490107 Yan J , et al. (2008)
c.83G>C p.Gly28Ala missense_variant Unknown - Unknown 18490107 Yan J , et al. (2008)
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 - - - 18940311 Vrijenhoek T , et al. (2008)
- - copy_number_loss - - - 18940311 Vrijenhoek T , et al. (2008)
- - copy_number_gain - - - 18940311 Vrijenhoek T , et al. (2008)
- - copy_number_loss - - - 18940311 Vrijenhoek T , et al. (2008)
- - copy_number_loss - - - 18940311 Vrijenhoek T , et al. (2008)
- - copy_number_loss - - - 18945720 Rujescu D , et al. (2008)
- - copy_number_loss - - - 18945720 Rujescu D , et al. (2008)
- - copy_number_loss - - - 18945720 Rujescu D , et al. (2008)
- - copy_number_loss - - - 18945720 Rujescu D , et al. (2008)
- - copy_number_loss - - - 18945720 Rujescu D , et al. (2008)
- - copy_number_loss - - - 18945720 Rujescu D , et al. (2008)
- - copy_number_loss - - - 18945720 Rujescu D , et al. (2008)
- - copy_number_loss - - - 18945720 Rujescu D , et al. (2008)
- - copy_number_loss - - - 18945720 Rujescu D , et al. (2008)
- - copy_number_loss - - - 18945720 Rujescu D , et al. (2008)
- - copy_number_loss - - - 18945720 Rujescu D , et al. (2008)
- - copy_number_loss - - - 18945720 Rujescu D , et al. (2008)
- - copy_number_loss - - - 18945720 Rujescu D , et al. (2008)
- - copy_number_loss - - - 18945720 Rujescu D , et al. (2008)
- - copy_number_loss Familial Maternal Simplex 19896112 Zweier C , et al. (2009)
c.2936C>G p.Ser979Ter stop_gained Familial Paternal Simplex 19896112 Zweier C , et al. (2009)
- - copy_number_loss Familial Maternal Multi-generational 20162629 Winiowiecka-Kowalnik B , et al. (2010)
- - copy_number_gain Familial Maternal Possibly multi-generational 20162629 Winiowiecka-Kowalnik B , et al. (2010)
- - copy_number_gain Unknown Not maternal Simplex 20162629 Winiowiecka-Kowalnik B , et al. (2010)
- - copy_number_loss Unknown Not maternal Simplex 20468056 Ching MS , et al. (2010)
- - copy_number_loss De novo - Simplex 20468056 Ching MS , et al. (2010)
- - copy_number_loss Familial Paternal Simplex 20468056 Ching MS , et al. (2010)
- - copy_number_loss Familial Paternal Simplex 20468056 Ching MS , et al. (2010)
- - copy_number_loss De novo - Simplex 20468056 Ching MS , et al. (2010)
- - 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 De novo - Simplex 20468056 Ching MS , et al. (2010)
- - copy_number_loss Unknown - Simplex 20468056 Ching MS , et al. (2010)
- - copy_number_loss De novo - Simplex 20468056 Ching MS , et al. (2010)
- - copy_number_loss Familial Maternal Simplex 20468056 Ching MS , et al. (2010)
- - copy_number_loss Familial Maternal Simplex 20468056 Ching MS , et al. (2010)
- - copy_number_gain De novo - Simplex 20531469 Pinto D , et al. (2010)
- - copy_number_loss De novo - Unknown 20531469 Pinto D , et al. (2010)
- - copy_number_loss De novo - Unknown 20531469 Pinto D , et al. (2010)
- - copy_number_loss De novo - Unknown 20531469 Pinto D , et al. (2010)
- - copy_number_loss Familial Paternal - 20531469 Pinto D , et al. (2010)
- - copy_number_loss Familial Maternal - 20531469 Pinto D , et al. (2010)
- - copy_number_loss Familial Maternal - 20531469 Pinto D , et al. (2010)
- - copy_number_loss Familial Maternal - 20531469 Pinto D , et al. (2010)
ins(ACGG) p.Gly1402AspfsTer29 frameshift_variant De novo - - 20797689 Awadalla P , et al. (2010)
c.4205insACGG - frameshift_variant De novo - - 21424692 Gauthier J , et al. (2011)
- - copy_number_loss Familial Paternal - 21827697 Gregor A , et al. (2011)
- - copy_number_loss Familial Maternal - 21827697 Gregor A , et al. (2011)
- - 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 Familial Paternal - 21827697 Gregor A , et al. (2011)
- - copy_number_loss De novo - - 21827697 Gregor A , et al. (2011)
- - copy_number_loss Familial Maternal Multiplex 21964664 Harrison V , et al. (2011)
- - copy_number_loss Familial Paternal Multiplex 21964664 Harrison V , et al. (2011)
- - copy_number_loss Familial Maternal Multi-generational 22337556 Duong L , et al. (2012)
c.2880-1G>A - splice_site_variant Familial Paternal Multi-generational 22337556 Duong L , et al. (2012)
c.705C>G p.(=) synonymous_variant Unknown - - 22405623 Liu Y , et al. (2012)
c.844T>C p.Tyr282His missense_variant Familial Maternal - 22405623 Liu Y , et al. (2012)
c.2677C>G p.Leu893Val missense_variant Familial Paternal - 22405623 Liu Y , et al. (2012)
c.3403A>G p.Ile1135Val missense_variant Familial Paternal - 22405623 Liu Y , et al. (2012)
c.81A>G p.(=) synonymous_variant Unknown - - 22405623 Liu Y , et al. (2012)
c.132C>T p.(=) synonymous_variant Unknown - - 22405623 Liu Y , et al. (2012)
c.-3G>T - 5_prime_UTR_variant Familial - - 22504536 Camacho-Garcia RJ , et al. (2012)
c.3G>T p.Met1? initiator_codon_variant Familial - - 22504536 Camacho-Garcia RJ , et al. (2012)
c.1124G>A p.Arg375Gln missense_variant Familial Maternal Multiplex 22504536 Camacho-Garcia RJ , et al. (2012)
c.1132G>A p.Gly378Ser missense_variant Familial Maternal Simplex 22504536 Camacho-Garcia RJ , et al. (2012)
c.2865T>A p.Tyr955Ter stop_gained De novo - Simplex 22542183 Iossifov I , et al. (2012)
- - 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 - - 22617343 Schaaf CP , et al. (2012)
- - copy_number_loss Inherited Paternal - 22617343 Schaaf CP , et al. (2012)
- - copy_number_loss Inherited Maternal - 22617343 Schaaf CP , et al. (2012)
- - copy_number_loss De novo - - 22617343 Schaaf CP , et al. (2012)
- - copy_number_loss Inherited Maternal - 22617343 Schaaf CP , et al. (2012)
- - copy_number_loss Unknown - - 22617343 Schaaf CP , et al. (2012)
- - copy_number_loss Unknown - - 22617343 Schaaf CP , et al. (2012)
- - copy_number_loss Inherited Maternal - 22617343 Schaaf CP , et al. (2012)
- - copy_number_loss Inherited Maternal Multiplex 22617343 Schaaf CP , et al. (2012)
- - copy_number_loss Inherited Paternal - 22617343 Schaaf CP , et al. (2012)
- - copy_number_loss Inherited Maternal - 22617343 Schaaf CP , et al. (2012)
- - copy_number_loss Inherited Maternal - 22617343 Schaaf CP , et al. (2012)
- - copy_number_loss Inherited Paternal Multiplex 22617343 Schaaf CP , et al. (2012)
- - copy_number_loss Unknown (not maternal) - - 22617343 Schaaf CP , et al. (2012)
- - 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 Paternal - 22617343 Schaaf CP , et al. (2012)
- - copy_number_loss Familial Paternal - 22617343 Schaaf CP , et al. (2012)
- - copy_number_loss Familial Maternal - 22617343 Schaaf CP , et al. (2012)
- - copy_number_loss Familial Paternal - 22617343 Schaaf CP , et al. (2012)
c.83G>C p.Gly28Ala missense_variant Unknown - - 22892527 Boccuto L , et al. (2012)
c.337C>T p.Arg113Ter stop_gained De novo - - 22914163 Kong A , et al. (2012)
- - copy_number_loss Familial Paternal Multi-generational 23207424 Bermudez-Wagner K , et al. (2012)
- - copy_number_loss Familial Maternal Unknown 23275889 Prasad A , et al. (2013)
- - 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 Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_loss Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_loss Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_loss Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_loss Familial Maternal Multi-generational 23294455 Mller RS , et al. (2013)
- - copy_number_loss Familial Paternal Multiplex 23294455 Mller RS , et al. (2013)
- - copy_number_loss Familial Paternal Simplex 23294455 Mller RS , et al. (2013)
- - copy_number_loss De novo - Multiplex 23294455 Mller RS , et al. (2013)
- - copy_number_loss De novo - Multiplex 23294455 Mller RS , et al. (2013)
- - copy_number_loss De novo - Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss Familial Maternal Multiplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss Familial Maternal Multiplex 23375656 Girirajan S , 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)
- - copy_number_loss Familial Paternal Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss De novo - Simplex 23375656 Girirajan S , et al. (2013)
- - 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 - - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Familial Paternal - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Familial Maternal Multiplex 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Familial Paternal - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Unknown - - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Unknown - - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss De novo - - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Unknown - - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Familial Paternal - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Familial Maternal - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Unknown - - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Familial Paternal - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Unknown - - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Unknown - - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Unknown - - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Unknown - - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Unknown - - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Unknown - - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Familial Paternal - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Unknown - - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Familial Paternal - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Unknown - - 23495017 Dabell MP , et al. (2013)
- - 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 - - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss De novo - Multiplex 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Familial Maternal - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Unknown - - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Unknown - - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Unknown - - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Unknown - Multiplex 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Unknown - Multiplex 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Unknown - - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Familial Paternal - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Unknown - - 23495017 Dabell MP , et al. (2013)
- - copy_number_loss Familial Maternal Multiplex 23505263 Van Den Bossche MJ , et al. (2013)
- - copy_number_loss De novo - - 23533028 Bna F , et al. (2013)
- - copy_number_loss Apparently de novo - - 23533028 Bna F , et al. (2013)
- - copy_number_loss De novo - - 23533028 Bna F , et al. (2013)
- - copy_number_loss Unknown (not maternal) - - 23533028 Bna F , et al. (2013)
- - copy_number_loss Familial Maternal Possibly multi-generational 23533028 Bna F , et al. (2013)
- - copy_number_loss Unknown - - 23533028 Bna F , et al. (2013)
- - copy_number_loss Familial Maternal Possibly multi-generational 23533028 Bna F , et al. (2013)
- - copy_number_loss Unknown - - 23533028 Bna F , et al. (2013)
- - copy_number_loss Familial Maternal Possibly multi-generational 23533028 Bna F , et al. (2013)
- - copy_number_loss Apparently de novo - - 23533028 Bna F , et al. (2013)
- - copy_number_loss Unknown - - 23533028 Bna F , et al. (2013)
- - copy_number_loss Familial Paternal Possibly multi-generational 23533028 Bna F , et al. (2013)
- - copy_number_loss Unknown - - 23533028 Bna F , et al. (2013)
- - copy_number_loss Unknown (not maternal) - Multiplex 23533028 Bna F , et al. (2013)
- - copy_number_loss Familial Maternal - 23533028 Bna F , et al. (2013)
- - copy_number_loss De novo - - 23533028 Bna F , et al. (2013)
- - copy_number_loss Unknown (not maternal) - - 23533028 Bna F , et al. (2013)
- - 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)
- - copy_number_loss De novo - - 23533028 Bna F , et al. (2013)
- - copy_number_loss Familial Maternal Multi-generational 23533028 Bna F , et al. (2013)
- - copy_number_loss Unknown - - 23533028 Bna F , et al. (2013)
- - copy_number_loss Familial Paternal - 23533028 Bna F , et al. (2013)
- - copy_number_loss Familial Paternal Multi-generational 23533028 Bna F , et al. (2013)
- - copy_number_loss Unknown - - 23533600 Nag A , et al. (2013)
- - copy_number_loss Familial Parental Multi-generational 23533600 Nag A , et al. (2013)
- - copy_number_loss De novo - Simplex 23533600 Nag A , et al. (2013)
- - copy_number_loss De novo - Multi-generational 23533600 Nag A , et al. (2013)
c.2653C>T p.His885Tyr missense_variant Familial Paternal Multiplex 23849776 Jiang YH , et al. (2013)
- - copy_number_loss Familial Maternal Multiplex 23879678 Walker S and Scherer SW (2013)
- - copy_number_loss Unknown - Simplex 23879678 Walker S and Scherer SW (2013)
- - copy_number_loss Unknown - Simplex 23879678 Walker S and Scherer SW (2013)
- - copy_number_loss Unknown - Simplex 23879678 Walker S and Scherer SW (2013)
- - 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.455G>A p.Gly152Asp missense_variant Unknown - Unknown 24066114 Koshimizu E , et al. (2013)
c.972C>G p.Tyr324Ter stop_gained Unknown - Unknown 24126932 Hu X , et al. (2013)
c.607A>T p.Lys203Ter stop_gained Unknown - Unknown 24126932 Hu X , et al. (2013)
- - copy_number_loss Familial Both parents Simplex 24508361 Utine GE , et al. (2014)
- - copy_number_loss Unknown - Multiplex 25149956 Imitola J , et al. (2014)
- - copy_number_loss Unknown - Multiplex 25149956 Imitola J , et al. (2014)
- - copy_number_loss 4 de novo, 8 inherited, 18 unknown - Unknown 25217958 Coe BP , et al. (2014)
c.3763G>A p.Val1255Ile missense_variant De novo - Simplex 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.308C>T p.Thr103Ile missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1945C>T p.Arg649Trp missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1691A>G p.Arg564Gly missense_variant Familial Paternal Multiplex 25363760 De Rubeis S , et al. (2014)
del(AC) - frameshift_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.2166G>T p.Gln722His 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.302C>T p.Thr101Met 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)
c.2725C>A p.Leu909Met missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
- - copy_number_loss;copy_number_loss Familial Both parents Simplex 25486015 Holmquist P (2014)
c.2437C>T p.Arg813Cys missense_variant Familial Paternal Multi-generational 25533962 Deciphering Developmental Disorders Study (2014)
- - copy_number_loss De novo - Simplex 25614873 Vias-Jornet M , et al. (2015)
- - copy_number_loss Familial Maternal Multi-generational 25614873 Vias-Jornet M , et al. (2015)
- - copy_number_loss Familial Maternal Multi-generational 25614873 Vias-Jornet M , et al. (2015)
- - copy_number_loss De novo - - 26325558 Tammimies K , et al. (2015)
- - copy_number_loss Familial Maternal Multiplex 27018473 Brandler WM , et al. (2016)
c.3018del p.Phe1006LeufsTer26 frameshift_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.3308C>T p.Pro1103Leu missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.2573G>A p.Gly858Glu 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_gain De novo - - 27841880 Redin C , et al. (2016)
- - complex_structural_alteration Familial Paternal Multi-generational 27841880 Redin C , et al. (2016)
c.4166_4167delCCinsC p.Cys1390ValfsTer23 frameshift_variant De novo - Simplex 28191889 Stessman HA , et al. (2017)
c.41C>T p.Ser14Leu missense_variant Familial Paternal Simplex 28289584 Onay H , et al. (2017)
c.2242C>A p.Leu748Ile missense_variant Familial Paternal Multi-generational 28289584 Onay H , et al. (2017)
- - copy_number_loss Familial Paternal Simplex 28649445 Woodbury-Smith M , et al. (2017)
c.2110G>A p.Gly704Arg missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.3333G>A p.Met1111Ile missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.64G>C p.Gly22Arg missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
- - loss_of_function_variant De novo - - 29754769 Liu Y , et al. (2018)
- - missense_variant De novo - - 29754769 Liu Y , et al. (2018)
- - splicing_variant De novo - - 29754769 Liu Y , et al. (2018)
Common Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.511C>T p.(=) synonymous_variant - - - 18179900 Kim HG , et al. (2008)
c.999C>T;c.900C>T;c.840C>T;c.105C>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
2

Strong Candidate

2

Score Delta: Score remained at 2.1

2

Strong Candidate

See all Category 2 Genes

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

10/1/2017
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
[The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016] [Mutations in NRXN1 in a family multiply affected with brain disorders: NRXN1 mutations and brain disorders.2012] [Neurexin regulates visual function via mediating retinoid transport to promote rhodopsin maturation.2013] [Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders.2010] [Neurexin-1 and frontal lobe white matter: an overlapping intermediate phenotype for schizophrenia and autism spectrum disorders.2011] [Recurrent CNVs disrupt three candidate genes in schizophrenia patients.2008] [Mutation analysis of the NRXN1 gene in a Chinese autism cohort.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] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Etiological yield of SNP microarrays in idiopathic intellectual disability.2014] [Frequency and Complexity of De Novo Structural Mutation in Autism.2016] [Mutation analysis of the NRXN1 gene in autism spectrum disorders.2017] [Direct measure of the de novo mutation rate in autism and schizophrenia cohorts.2010] [Refining analyses of copy number variation identifies specific genes associated with developmental delay.2014] [Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia.2011] [Functional impact of global rare copy number variation in autism spectrum disorders.2010] [De novo gene disruptions in children on the autistic spectrum.2012] [Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.2013] [Identification of rare copy number variants in high burden schizophrenia families.2013] [Phenotypic spectrum and genotype-phenotype correlations of NRXN1 exon deletions.2012] [A patient with vertebral, cognitive and behavioural abnormalities and a de novo deletion of NRXN1alpha.2007] [A survey of rare coding variants in candidate genes in schizophrenia by deep sequencing.2013] [High frequency of neurexin 1beta signal peptide structural variants in patients with autism.2006] [Identification of candidate intergenic risk loci in autism spectrum disorder.2013] [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] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [Targeted combinatorial alternative splicing generates brain region-specific repertoires of neurexins.2014] [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] [Binding properties of neuroligin 1 and neurexin 1beta reveal function as heterophilic cell adhesion molecules.1997] [Mapping autism risk loci using genetic linkage and chromosomal rearrangements.2007] [Rate of de novo mutations and the importance of father's age to disease risk.2012] [Disruption of the neurexin 1 gene is associated with schizophrenia.2008] [Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017] [Compound heterozygous deletion of NRXN1 causing severe developmental delay with early onset epilepsy in two sisters.2011] [Modeling the functional genomics of autism using human neurons.2011] [Sensory regulation of neuroligins and neurexin I in the honeybee brain.2010] [Neurexins physically and functionally interact with GABA(A) receptors.2010] [Neuroligin-1 induces neurite outgrowth through interaction with neurexin-1 and activation of fibroblast growth factor receptor-1.2012] [Molecular characterization of NRXN1 deletions from 19,263 clinical microarray cases identifies exons important for neurodevelopmental disease expre...2016] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [CNV analysis in Tourette syndrome implicates large genomic rearrangements in COL8A1 and NRXN1.2013] [Presynaptic targeting of alpha4beta 2 nicotinic acetylcholine receptors is regulated by neurexin-1beta.2009] [2p16.3 microdeletion with partial deletion of the neurexin-1 gene in a female with developmental delays, short stature, and a congenital diaphragma...2012] [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] [Retrograde modulation of presynaptic release probability through signaling mediated by PSD-95-neuroligin.2007] [Investigation of NRXN1 deletions: clinical and molecular characterization.2013] [Functional impacts of NRXN1 knockdown on neurodevelopment in stem cell models.2013] [Disruption of neurexin 1 associated with autism spectrum disorder.2008] [A boy with dysmorphic features, intellectual disability, and biallelic homozygous deletion in NRXN1.2014] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Mutations affecting synaptic levels of neurexin-1 in autism and mental retardation.2012] [Alternative splicing controls selective trans-synaptic interactions of the neuroligin-neurexin complex.2006] [Mouse neurexin-1alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments.2009] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Silencing of neuroligin function by postsynaptic neurexins.2007] [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] [Trans-synaptic interaction of GluRdelta2 and Neurexin through Cbln1 mediates synapse formation in the cerebellum.2010] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Splice form dependence of beta-neurexin/neuroligin binding interactions.2010] [Neurexin mediates the assembly of presynaptic terminals.2003] [Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1.2011] [Intragenic rearrangements in NRXN1 in three families with autism spectrum disorder, developmental delay, and speech delay.2010] [Neurexin 1alpha structural variants associated with autism.2008] [Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion.2012] [Fraternal twins with autism, severe cognitive deficit, and epilepsy: diagnostic role of chromosomal microarray analysis.2014]
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
[Mutations in NRXN1 in a family multiply affected with brain disorders: NRXN1 mutations and brain disorders.2012] [Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders.2010] [Recurrent CNVs disrupt three candidate genes in schizophrenia patients.2008] [Neurexin-1 and frontal lobe white matter: an overlapping intermediate phenotype for schizophrenia and autism spectrum disorders.2011] [Mutation analysis of the NRXN1 gene in a Chinese autism cohort.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 1 (NRXN1) splice isoform expression during human neocortical development and aging.2015] [Etiological yield of SNP microarrays in idiopathic intellectual disability.2014] [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] [Refining analyses of copy number variation identifies specific genes associated with developmental delay.2014] [Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.2015] [Functional impact of global rare copy number variation in autism spectrum disorders.2010] [De novo gene disruptions in children on the autistic spectrum.2012] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.2013] [A patient with vertebral, cognitive and behavioural abnormalities and a de novo deletion of NRXN1alpha.2007] [A survey of rare coding variants in candidate genes in schizophrenia by deep sequencing.2013] [Phenotypic spectrum and genotype-phenotype correlations of NRXN1 exon deletions.2012] [High frequency of neurexin 1beta signal peptide structural variants in patients with autism.2006] [Identification of candidate intergenic risk loci in autism spectrum disorder.2013] [Targeted combinatorial alternative splicing generates brain region-specific repertoires of neurexins.2014] [Neurexins physically and functionally interact with GABA(A) receptors.2010] [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] [Binding properties of neuroligin 1 and neurexin 1beta reveal function as heterophilic cell adhesion molecules.1997] [Functional impacts of NRXN1 knockdown on neurodevelopment in stem cell models.2013] [Modeling the functional genomics of autism using human neurons.2011] [Mapping autism risk loci using genetic linkage and chromosomal rearrangements.2007] [Rate of de novo mutations and the importance of father's age to disease risk.2012] [Compound heterozygous deletion of NRXN1 causing severe developmental delay with early onset epilepsy in two sisters.2011] [Trans-synaptic interaction of GluRdelta2 and Neurexin through Cbln1 mediates synapse formation in the cerebellum.2010] [Sensory regulation of neuroligins and neurexin I in the honeybee brain.2010] [Molecular characterization of NRXN1 deletions from 19,263 clinical microarray cases identifies exons important for neurodevelopmental disease expre...2016] [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] [Neurexin regulates visual function via mediating retinoid transport to promote rhodopsin maturation.2013] [Disruption of the neurexin 1 gene is associated with schizophrenia.2008] [CNV analysis in Tourette syndrome implicates large genomic rearrangements in COL8A1 and NRXN1.2013] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Neuroligin-1 induces neurite outgrowth through interaction with neurexin-1 and activation of fibroblast growth factor receptor-1.2012] [Silencing of neuroligin function by postsynaptic neurexins.2007] [2p16.3 microdeletion with partial deletion of the neurexin-1 gene in a female with developmental delays, short stature, and a congenital diaphragma...2012] [Retrograde modulation of presynaptic release probability through signaling mediated by PSD-95-neuroligin.2007] [A common cognitive, psychiatric, and dysmorphic phenotype in carriers of NRXN1 deletion.2015] [Investigation of NRXN1 deletions: clinical and molecular characterization.2013] [A boy with dysmorphic features, intellectual disability, and biallelic homozygous deletion in NRXN1.2014] [Disruption of neurexin 1 associated with autism spectrum disorder.2008] [Identification of rare copy number variants in high burden schizophrenia families.2013] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Mutations affecting synaptic levels of neurexin-1 in autism and mental retardation.2012] [Mouse neurexin-1alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments.2009] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature.2013] [Fraternal twins with autism, severe cognitive deficit, and epilepsy: diagnostic role of chromosomal microarray analysis.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Splice form dependence of beta-neurexin/neuroligin binding interactions.2010] [Neurexin mediates the assembly of presynaptic terminals.2003] [Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1.2011] [Presynaptic targeting of alpha4beta 2 nicotinic acetylcholine receptors is regulated by neurexin-1beta.2009] [Intragenic rearrangements in NRXN1 in three families with autism spectrum disorder, developmental delay, and speech delay.2010] [Neurexin 1alpha structural variants associated with autism.2008] [Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion.2012] [Alternative splicing controls selective trans-synaptic interactions of the neuroligin-neurexin complex.2006] [Frequency and Complexity of De Novo Structural Mutation in Autism.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
[Mutations in NRXN1 in a family multiply affected with brain disorders: NRXN1 mutations and brain disorders.2012] [Alternative splicing controls selective trans-synaptic interactions of the neuroligin-neurexin complex.2006] [Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders.2010] [Recurrent CNVs disrupt three candidate genes in schizophrenia patients.2008] [Neurexin-1 and frontal lobe white matter: an overlapping intermediate phenotype for schizophrenia and autism spectrum disorders.2011] [Mutation analysis of the NRXN1 gene in a Chinese autism cohort.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] [Etiological yield of SNP microarrays in idiopathic intellectual disability.2014] [Investigation of NRXN1 deletions: clinical and molecular characterization.2013] [Neurexin 1 (NRXN1) splice isoform expression during human neocortical development and aging.2015] [Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia.2011] [Direct measure of the de novo mutation rate in autism and schizophrenia cohorts.2010] [Refining analyses of copy number variation identifies specific genes associated with developmental delay.2014] [Functional impact of global rare copy number variation in autism spectrum disorders.2010] [Neurexin regulates visual function via mediating retinoid transport to promote rhodopsin maturation.2013] [De novo gene disruptions in children on the autistic spectrum.2012] [Neurexin mediates the assembly of presynaptic terminals.2003] [Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.2013] [A patient with vertebral, cognitive and behavioural abnormalities and a de novo deletion of NRXN1alpha.2007] [A survey of rare coding variants in candidate genes in schizophrenia by deep sequencing.2013] [Phenotypic spectrum and genotype-phenotype correlations of NRXN1 exon deletions.2012] [Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.2015] [High frequency of neurexin 1beta signal peptide structural variants in patients with autism.2006] [Neurexins physically and functionally interact with GABA(A) receptors.2010] [Identification of candidate intergenic risk loci in autism spectrum disorder.2013] [Targeted combinatorial alternative splicing generates brain region-specific repertoires of neurexins.2014] [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] [Binding properties of neuroligin 1 and neurexin 1beta reveal function as heterophilic cell adhesion molecules.1997] [Functional impacts of NRXN1 knockdown on neurodevelopment in stem cell models.2013] [Modeling the functional genomics of autism using human neurons.2011] [Mapping autism risk loci using genetic linkage and chromosomal rearrangements.2007] [Rate of de novo mutations and the importance of father's age to disease risk.2012] [Compound heterozygous deletion of NRXN1 causing severe developmental delay with early onset epilepsy in two sisters.2011] [Identification of rare copy number variants in high burden schizophrenia families.2013] [Sensory regulation of neuroligins and neurexin I in the honeybee brain.2010] [Trans-synaptic interaction of GluRdelta2 and Neurexin through Cbln1 mediates synapse formation in the cerebellum.2010] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [CNV analysis in Tourette syndrome implicates large genomic rearrangements in COL8A1 and NRXN1.2013] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Disruption of the neurexin 1 gene is associated with schizophrenia.2008] [2p16.3 microdeletion with partial deletion of the neurexin-1 gene in a female with developmental delays, short stature, and a congenital diaphragma...2012] [Neuroligin-1 induces neurite outgrowth through interaction with neurexin-1 and activation of fibroblast growth factor receptor-1.2012] [Retrograde modulation of presynaptic release probability through signaling mediated by PSD-95-neuroligin.2007] [A boy with dysmorphic features, intellectual disability, and biallelic homozygous deletion in NRXN1.2014] [Disruption of neurexin 1 associated with autism spectrum disorder.2008] [A common cognitive, psychiatric, and dysmorphic phenotype in carriers of NRXN1 deletion.2015] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [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] [Mouse neurexin-1alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments.2009] [Silencing of neuroligin function by postsynaptic neurexins.2007] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Mutations affecting synaptic levels of neurexin-1 in autism and mental retardation.2012] [Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature.2013] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Splice form dependence of beta-neurexin/neuroligin binding interactions.2010] [Fraternal twins with autism, severe cognitive deficit, and epilepsy: diagnostic role of chromosomal microarray analysis.2014] [Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1.2011] [Presynaptic targeting of alpha4beta 2 nicotinic acetylcholine receptors is regulated by neurexin-1beta.2009] [Intragenic rearrangements in NRXN1 in three families with autism spectrum disorder, developmental delay, and speech delay.2010] [Neurexin 1alpha structural variants associated with autism.2008] [Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion.2012]
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
[Mutations in NRXN1 in a family multiply affected with brain disorders: NRXN1 mutations and brain disorders.2012] [Alternative splicing controls selective trans-synaptic interactions of the neuroligin-neurexin complex.2006] [Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders.2010] [Neurexin-1 and frontal lobe white matter: an overlapping intermediate phenotype for schizophrenia and autism spectrum disorders.2011] [Disruption of the neurexin 1 gene is associated with schizophrenia.2008] [Mutation analysis of the NRXN1 gene in a Chinese autism cohort.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] [Etiological yield of SNP microarrays in idiopathic intellectual disability.2014] [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] [Refining analyses of copy number variation identifies specific genes associated with developmental delay.2014] [Functional impact of global rare copy number variation in autism spectrum disorders.2010] [Neurexin regulates visual function via mediating retinoid transport to promote rhodopsin maturation.2013] [De novo gene disruptions in children on the autistic spectrum.2012] [Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.2013] [A patient with vertebral, cognitive and behavioural abnormalities and a de novo deletion of NRXN1alpha.2007] [A survey of rare coding variants in candidate genes in schizophrenia by deep sequencing.2013] [Phenotypic spectrum and genotype-phenotype correlations of NRXN1 exon deletions.2012] [High frequency of neurexin 1beta signal peptide structural variants in patients with autism.2006] [Neurexin 1 (NRXN1) splice isoform expression during human neocortical development and aging.2015] [Identification of candidate intergenic risk loci in autism spectrum disorder.2013] [A boy with dysmorphic features, intellectual disability, and biallelic homozygous deletion in NRXN1.2014] [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] [Binding properties of neuroligin 1 and neurexin 1beta reveal function as heterophilic cell adhesion molecules.1997] [Functional impacts of NRXN1 knockdown on neurodevelopment in stem cell models.2013] [Mapping autism risk loci using genetic linkage and chromosomal rearrangements.2007] [Rate of de novo mutations and the importance of father's age to disease risk.2012] [Compound heterozygous deletion of NRXN1 causing severe developmental delay with early onset epilepsy in two sisters.2011] [Targeted combinatorial alternative splicing generates brain region-specific repertoires of neurexins.2014] [Sensory regulation of neuroligins and neurexin I in the honeybee brain.2010] [Presynaptic targeting of alpha4beta 2 nicotinic acetylcholine receptors is regulated by neurexin-1beta.2009] [CNV analysis in Tourette syndrome implicates large genomic rearrangements in COL8A1 and NRXN1.2013] [Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut...2013] [Recurrent CNVs disrupt three candidate genes in schizophrenia patients.2008] [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] [Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.2015] [2p16.3 microdeletion with partial deletion of the neurexin-1 gene in a female with developmental delays, short stature, and a congenital diaphragma...2012] [Retrograde modulation of presynaptic release probability through signaling mediated by PSD-95-neuroligin.2007] [Modeling the functional genomics of autism using human neurons.2011] [Disruption of neurexin 1 associated with autism spectrum disorder.2008] [Silencing of neuroligin function by postsynaptic neurexins.2007] [Trans-synaptic interaction of GluRdelta2 and Neurexin through Cbln1 mediates synapse formation in the cerebellum.2010] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Mouse neurexin-1alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments.2009] [A common cognitive, psychiatric, and dysmorphic phenotype in carriers of NRXN1 deletion.2015] [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] [Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature.2013] [Identification of rare copy number variants in high burden schizophrenia families.2013] [Mutations affecting synaptic levels of neurexin-1 in autism and mental retardation.2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Splice form dependence of beta-neurexin/neuroligin binding interactions.2010] [Neurexins physically and functionally interact with GABA(A) receptors.2010] [Neurexin mediates the assembly of presynaptic terminals.2003] [Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1.2011] [Fraternal twins with autism, severe cognitive deficit, and epilepsy: diagnostic role of chromosomal microarray analysis.2014] [Intragenic rearrangements in NRXN1 in three families with autism spectrum disorder, developmental delay, and speech delay.2010] [Neurexin 1alpha structural variants associated with autism.2008] [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]
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.

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
[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] [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]
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 57 Deletion-Duplication 94  /  437
Animal Models associated with NRXN1(2 Models)
NRXN1_1_HM 1 Genetic Mus musculus
NRXN1_1_KO_HM 1 Genetic Mus musculus
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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