NLGN4X
protein-codingneuroligin 4 X-linked, the group of Neuroligins
Gene summary
This gene encodes a member of the type-B carboxylesterase/lipase protein family. The encoded protein belongs to a family of neuronal cell surface proteins. Members of this family may act as splice site-specific ligands for beta-neurexins and may be involved in the formation and remodeling of central nervous system synapses. The encoded protein interacts with discs large homolog 4 (DLG4). Mutations in this gene have been associated with autism and Asperger syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]
- NLGN4
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~388.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0010341
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0100148
Submitter: ClinGen
*NLGN4X* was first reported in relation to X-linked complex neurodevelopmental disorder in 2003 (Jamain et al., PMID: 12669065). Since then, multiple variants have been reported, including nonsense, frameshift, splice, missense, and large deletion variants. The observed phenotypes in affected males include autism spectrum disorder and/or intellectual disability; attention deficit-hyperactivity disorder is also reported in some individuals. Carrier females are typically unaffected. Nine variants (nonsense, frameshift, splice, missense, and exonic deletion) that have been reported in nine probands in eight publications (PMIDs: 12669065, 14963808, 16648374, 18231125, 19726642, 23352163, 26350204, 28263302) are included in this curation. Variants in this gene were reported to segregate with disease in a large family with 13 affected males (PMID: 14963808). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. In humans, neuroligin 4 (NLGN4) is encoded by two genes, *NLGN4X* and *NLGN4Y*, that are localized on the sex chromosomes. NLGN4 is a member of the neuroligin family of neuronal cell-adhesion molecules that are localized postsynaptically, interact with presynaptic neurexins, and play a key role in the maturation and function of synapses. This gene-disease relationship is also supported by mouse models displaying neurodevelopmental phenotypes consistent with autism, functional studies, and protein interaction with neurexins (PMIDs: 21278334, 23183221, 24104404, 29106499). In humans, NLGN4 is preferentially expressed in the cortex, whereas mouse Nlgn4 is primarily expressed in the brainstem, retina, and spinal cord. Additionally, in human neurons NLGN4 is preferentially localized to excitatory synapses and only a subset of inhibitory synapses, whereas in mice Nlgn4 is primarily present in glycinergic and GABAergic synapses. These differences, along with the poor conservation of the mouse ortholog of *NLGN4*, called Nlgn4-like (*Nlgn4l*), should be considered when interpreting the relevance of the results obtained in knockout mice. In summary, there is definitive evidence supporting the relationship between *NLGN4X* and X-linked complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 1, 2018. It was reevaluated on October 10, 2025 (SOP Version 11). Although new evidence was added, the classification did not change.
Inheritance Pattern: XL
Disease ID:MONDO:0010341
Submitter: Ambry Genetics
Inheritance Pattern: XL
Disease ID:MONDO:0010341
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0010341
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: 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 NLGN4X variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_181332.3. 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 | 16 | 67 | 5 | 88 | ||
| missense | 2 | 234 | 22 | 258 | ||
| nonsense | 1 | 2 | 5 | 8 | ||
| start loss | 0 | |||||
| frameshift | 3 | 3 | 6 | |||
| splice donor/acceptor (+/-2bp) | 2 | 6 | 8 | |||
| Total | 6 | 4 | 264 | 89 | 5 | 368 |
Highest pathogenic variant AF is 0.0000018211819
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_851849.1 | 5 | MANE Select | |
| Ensembl | ENSP00000370485.3 | 5 | MANE Select | |
| RefSeq | NP_001269074.1 | 5 | Standard | |
| RefSeq | NP_001269075.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cell adhesion molecules (CAMs) - Homo sapiens (human)
- Neuronal System
- Neurexins and neuroligins
- Protein-protein interactions at synapses
Biological Process
- brainstem development
- neuron cell-cell adhesion
- learning
- cerebellum development
- neuron differentiation
Molecular Function
- protein binding
- chloride ion binding
- signaling receptor activity
- neurexin family protein binding
- protein homodimerization activity
Cellular Component
- plasma membrane
- integral component of plasma membrane
- cell surface
- postsynaptic density
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000381095
- Coding exons
- 5
- Length
- 388227
- Individuals with no LoFs
- 125744
- Homozygous LoFs
- 1
- Heterozygous LoFs
- 2
- Defined
- 125747
- p
- 0.0000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.70 | 222 | 368 | 0.604 | 0.0000331 | 5371 |
| Missense (PolyPhen) | 105 | 213.71 | 0.49131 | 3005 | ||
| Synonymous | -1.51 | 193 | 168 | 1.15 | 0.0000173 | 1627 |
| Loss of Function | 3.84 | 1 | 19.1 | 0.0524 | 0.00000137 | 320 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000038 | 0.000026 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Putative neuronal cell surface protein involved in cell- cell-interactions.;
- Disease
- DISEASE: Asperger syndrome, X-linked, 2 (ASPGX2) [MIM:300497]: A syndrome with features similar to autism. Affected individuals exhibit qualitative impairment in social interaction, as manifest by impairment in the use of non-verbal behaviors such as eye-to- eye gaze, facial expression, body postures, and gestures, failure to develop appropriate peer relationships, and lack of social sharing or reciprocity. Patients also exhibit restricted, repetitive and stereotyped patterns of behavior, interests, and activities, including abnormal preoccupation with certain activities and inflexible adherence to routines or rituals. Asperger syndrome is primarily distinguished from autism by the higher cognitive abilities and a more normal and timely development of language and communicative phrases. {ECO:0000269|PubMed:14963808}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.227
Intolerance Scores
- LoFtool
- 0.149
- RVIS EVS
- -0.84
- RVIS percentile EVS
- 11.18
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.791
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |