NRXN1
protein-codingneurexin 1, the group of Neurexins|MicroRNA protein coding host genes
Gene summary
This gene encodes a single-pass type I membrane protein that belongs to the neurexin family. Neurexins are cell-surface receptors that bind neuroligins to form Ca(2+)-dependent neurexin/neuroligin complexes at synapses in the central nervous system. This complex is required for efficient neurotransmission and is involved in the formation of synaptic contacts. Three members of this gene family have been studied in detail and are estimated to generate over 3,000 variants through the use of two alternative promoters (alpha and beta) and extensive alternative splicing in each family member. Recently, a third promoter (gamma) was identified for this gene in the 3' region. Mutations in this gene are associated with Pitt-Hopkins-like syndrome-2 and may contribute to susceptibility to schizophrenia. [provided by RefSeq, Aug 2016]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~1,307.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013690
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0013690
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013690
Submitter: PanelApp Australia
Inheritance Pattern: Unknown
Disease ID:MONDO:0005090
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: ClinGen
Heterozygous variants in *NRXN1* have been reported in a variety of neurodevelopmental disorders, including intellectual disability (ID), epilepsy, and autism spectrum disorder. Therefore, this curation concerns the relationship between *NRXN1* and autosomal dominant complex neurodevelopmental disorder. The first *NRXN1* deletion was reported by the Autism Genome Project Consortium in 2007 (PMID: 17322880). At least 118 pathogenic or likely pathogenic variants have been reported in ClinVar, including deletions, intragenic duplications, and sequence variants. Because the copy number changes included in this curation are larger than 10 kb, they could not be entered into the Gene Curation Interface. Thus, the genetic evidence is summarized below. - Zahir et al. (2008, PMID: 18057082) reported a 12-year-old male proband with intellectual disability, autistic features, and severe language and motor impairments; this individual had a heterozygous *de novo* deletion of ~320 kb in *NRXN1* (chr2:50,799,281-51,120,644, hg18), and was given 2 points. - Agha et al. (2008, PMID: 26438105) reported a 28-year-old female proband with developmental delay, language delay, intellectual disability, and impaired social interactions, carrying a heterozygous *de novo* deletion of ~455 kb overlapping *NRXN1* (chr2:51,020,477-51,476,031, hg19); this individual was given 2 points. - Wisniowiecka-Kowalnik et al. (2010, PMID: 20162629) reported three families with *NRXN1* rearrangements. Family 1 received a score of 1.5 points for a ~380 kb deletion in *NRXN1* that was observed in all five affected members (chr2:50,034,351-50,413,346, hg18). Family 2 also received a score of 1.5 points for an inherited intragenic tandem duplication, found in all three affected individuals (chr2:50,011,487-50,195,746, hg18). Family 3 had an affected girl with an intragenic tandem duplication (chr2:50,106,413-50,437,234, hg18) of unknown inheritance and was given a score of 0.5. - Gregor et al. (2011, PMID: 21827697) reported six individuals with *NRXN1* deletions, four of which were scored and given 0.5 points each, due to limited phenotypic information (N1: chr2:50,806,393-51,208,000, hg18, paternal; N2: chr2:50,270,203-51,357,206, hg18, maternal; N5: chr2:50,861,527-51,090,563, hg18, paternal; N6: chr2:51,033,865-51,496,143, hg18, *de novo*). - Ching et al. (2010, PMID: 20468056) reported 12 individuals, eight of which were scored. Patient 2 had a 3.9 Mb *de novo* deletion (chr2:50,128,256-54,050,713, hg18) overlapping *NRXN1* and five other genes and was therefore given a score of 0. Patient 3 received a downgraded score of 0.1 point for a 315 kb inherited deletion (chr2:50,897,002-51,212,385, hg18) in light of a very mild neurodevelopmental phenotype. Patients 4, 5, 6, 7, and 9 all received scores of 0.5. Patients 4, 6, and 7 all had inherited deletions (chr2:50,936,914-51,167,934; chr2:51,059,410-51,316,396; chr2:51,090,504-51,212,385, hg18); patient 5 had a *de novo* deletion (chr2:50,920,082-51,059,469, hg18), but was downgraded due to a mild neurodevelopmental phenotype; and patient 9 had a deletion of unknown inheritance (chr2:50,689,280-50,853,329, hg18). The deletion in patient 10 (chr2:50,714,927-50,853,329, hg18) occurred *de novo* and only impacted an intron and was given a score of 0, since only exonic *NRXN1* variants are known to be pathogenic. In total, 12.1 points were awarded for genetic evidence. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Neurexins are presynaptic cell adhesion molecules that bind to postsynaptic ligands, such as neuroligins. They mediate signaling across the synapse and shape the properties of neural circuits by specifying synaptic functions. This gene-disease relationship is also supported by experimental evidence, including mouse and stem cell models. In summary, there is definitive evidence supporting the relationship between *NRXN1* and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on July 10, 2019 (SOP Version 6).
Inheritance Pattern: AR
Disease ID:MONDO:0013690
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0005260
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0013696
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NRXN1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001330078.2. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 15 | 549 | 11 | 575 | ||
| missense | 1055 | 31 | 1086 | |||
| nonsense | 15 | 15 | 4 | 34 | ||
| start loss | 1 | 1 | ||||
| frameshift | 22 | 8 | 7 | 37 | ||
| splice donor/acceptor (+/-2bp) | 3 | 14 | 7 | 24 | ||
| Total | 41 | 37 | 1088 | 580 | 11 | 1757 |
Highest pathogenic variant AF is 0.000014514209
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001317007.1 | 22 | MANE Select | |
| Ensembl | ENSP00000385017.2 | 22 | MANE Select | |
| RefSeq | NP_001129131.1 | 23 | Standard | |
| RefSeq | NP_001307085.1 | 3 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| nrxn1a | Danio rerio | Structure: caudal vein plexus Quality: malformed abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cell adhesion molecules (CAMs) - Homo sapiens (human)
- Extracellular matrix organization
- Neuronal System
- Neurexins and neuroligins
- Non-integrin membrane-ECM interactions
Biological Process
- neuron cell-cell adhesion
- chemical synaptic transmission
- neurotransmitter secretion
- axon guidance
- synapse assembly
Molecular Function
- calcium channel regulator activity
- calcium ion binding
- protein binding
- acetylcholine receptor binding
- signaling receptor activity
Cellular Component
- nucleolus
- endoplasmic reticulum
- plasma membrane
- integral component of plasma membrane
- cell surface
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000404971
- Coding exons
- 23
- Length
- 1114032
- Individuals with no LoFs
- 125731
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 17
- Defined
- 125748
- p
- 0.0000676
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.56 | 681 | 897 | 0.759 | 0.0000541 | 10084 |
| Missense (PolyPhen) | 212 | 368.05 | 0.57601 | 4246 | ||
| Synonymous | -3.35 | 451 | 369 | 1.22 | 0.0000253 | 3017 |
| Loss of Function | 6.44 | 10 | 66.8 | 0.150 | 0.00000378 | 796 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00018 | 0.00016 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000080 | 0.000070 | rare |
| South Asian | 0.00014 | 0.00013 | rare |
| Other | 0.00020 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Neuronal cell surface protein that may be involved in cell recognition and cell adhesion by forming intracellular junctions through binding to neuroligins. May play a role in formation or maintenance of synaptic junctions. May mediate intracellular signaling. May play a role in angiogenesis (By similarity). {ECO:0000250}.;
Intolerance Scores
- LoFtool
- 0.297
- RVIS EVS
- -1.79
- RVIS percentile EVS
- 2.25
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.909
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |