NLGN4X

Summary

NLGN4X (neuroligin 4 X-linked, HGNC:14287) is a protein-coding gene on chromosome Xp22.32-p22.31, encoding Neuroligin-4, X-linked (Q8N0W4). Cell surface protein involved in cell-cell-interactions via its interactions with neurexin family members.

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.

Source: NCBI Gene 57502 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked complex neurodevelopmental disorder (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 390 total — 10 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 20
• Dosage sensitivity (ClinGen): haploinsufficiency emerging evidence, triplosensitivity no evidence
• MANE Select transcript: NM_181332

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14287
Approved symbol	NLGN4X
Name	neuroligin 4 X-linked
Location	Xp22.32-p22.31
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1260, NLGN, HLNX
Ensembl gene	ENSG00000146938
Ensembl biotype	protein_coding
OMIM	300427
Entrez	57502

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 14 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000275857, ENST00000381092, ENST00000381093, ENST00000381095, ENST00000469740, ENST00000477079, ENST00000483337, ENST00000538097, ENST00000899710, ENST00000899711, ENST00000899712, ENST00000899713, ENST00000899714, ENST00000915395, ENST00000915396

RefSeq mRNA: 4 — MANE Select: NM_181332 NM_001282145, NM_001282146, NM_020742, NM_181332

CCDS: CCDS14126

Canonical transcript exons

ENST00000381095 — 6 exons

Exon	Start	End
ENSE00001487515	6150995	6151771
ENSE00001487516	6228541	6228867
ENSE00001648911	5903077	5903866
ENSE00001655655	5909054	5909239
ENSE00001803933	6029280	6029432
ENSE00001827176	5890042	5893666

Expression profiles

Bgee: expression breadth ubiquitous, 223 present calls, max score 94.27.

FANTOM5 (CAGE): breadth broad, TPM avg 5.4219 / max 384.0114, expressed in 477 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
198350	3.9577	335
198348	1.0769	428
198347	0.2336	145
198349	0.1537	103

Top tissues by expression

285 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	94.27	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.06	gold quality
dorsal root ganglion	UBERON:0000044	93.09	gold quality
cerebellar vermis	UBERON:0004720	91.02	gold quality
entorhinal cortex	UBERON:0002728	90.25	gold quality
ventricular zone	UBERON:0003053	90.17	gold quality
secondary oocyte	CL:0000655	89.62	gold quality
decidua	UBERON:0002450	89.11	gold quality
Brodmann (1909) area 46	UBERON:0006483	88.92	gold quality
buccal mucosa cell	CL:0002336	88.51	gold quality
endothelial cell	CL:0000115	88.41	gold quality
postcentral gyrus	UBERON:0002581	88.35	gold quality
primary visual cortex	UBERON:0002436	88.29	gold quality
germinal epithelium of ovary	UBERON:0001304	87.98	gold quality
superior frontal gyrus	UBERON:0002661	87.70	gold quality
trigeminal ganglion	UBERON:0001675	87.53	gold quality
parietal lobe	UBERON:0001872	87.40	gold quality
lateral nuclear group of thalamus	UBERON:0002736	86.78	gold quality
occipital lobe	UBERON:0002021	86.73	gold quality
CA1 field of hippocampus	UBERON:0003881	86.72	gold quality
orbitofrontal cortex	UBERON:0004167	85.69	gold quality
ganglionic eminence	UBERON:0004023	85.68	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.24	gold quality
embryo	UBERON:0000922	84.34	gold quality
oocyte	CL:0000023	82.45	gold quality
temporal lobe	UBERON:0001871	82.40	gold quality
pons	UBERON:0000988	81.95	gold quality
cerebral cortex	UBERON:0000956	81.91	gold quality
sural nerve	UBERON:0015488	81.83	gold quality
prefrontal cortex	UBERON:0000451	81.72	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	61.61
E-HCAD-25	yes	16.68
E-ANND-3	yes	5.57

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, ZNF804A

miRNA regulators (miRDB)

95 targeting NLGN4X, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-153-5P	99.89	73.86	6317

Functional genomics

ClinGen dosage: haploinsufficiency 2 (emerging evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 36)

• report mutations in two X-linked genes encoding neuroligins NLGN3 and NLGN4 in siblings with autism-spectrum disorders (PMID:12669065)
• Scanning and sequencing of 2.5Mb of the NLGN4 genes reveals an association of NLGN4 structural variants at highly conserved amino acids with an estimated attributable risk for autism of about 3% in the cohorts studies. (PMID:15622415)
• Neuroligin mutations most probably represent rare causes of autism; it is unlikely that the allelic variants in any of these genes would be major risk factors for autism. (PMID:16077734)
• Data indicate that coding mutations in neuroligin 4 are very rarely associated to autism spectrum disorders. (PMID:16508939)
• Splice variants of the NLGN4 gene are associated with autism. (PMID:16648374)
• Syntrophin-gamma2 (SNTG2) is a de novo binding partner of X-linked neuroligin 4, which correlates with autism-related mutations. (PMID:17292328)
• no evidence for an involvement of NLGN3 and NLGN4X genetic variants with autism spectrum disorder on high functioning level (PMID:18189281)
• NLGN4 mutations can be associated with a wide spectrum of neuropsychiatric conditions and that carriers may be affected with milder symptoms (PMID:18231125)
• The results suggest a positive association between the genetic variants of the NLGN4 and NSMR in the Chinese children from Qinba Mountains Region. (PMID:19125102)
• This study indicated that the phenotypic spectrum of NLGN4X mutations and overexpressed NLGN4X transcript is associated with autism and nonsyndromic mental profound mental retardation. (PMID:19545860)
• NLGN4X gene is associated with autistic traits, empathy, and Asperger syndrome. (PMID:19598235)
• finding further contributes to consideration of neuroligins as probable candidate genes for future molecular genetic studies, suggesting that a defect of synaptogenesis may predispose to autism (PMID:19645625)
• Two brothers with classical autism spectrum disorder carry a single amino-acid substitution in neuroligin 4 (Arg87Trp). The substitution is absent from the brothers’ asymptomatic parents, suggesting that it arose in the maternal germ line. (PMID:19726642)
• Results suggest that unique conformational reshaping of the neuroligin 4 surface is required to permit neurexin 1beta association. (PMID:20543817)
• results indicate that the genetic variants located in NLGN4 can affect the cognitive abilities of boys. (PMID:20714171)
• The autism-associated DeltaE4 mutation in NLGN4 compromises the ability of NLGN4 to localize correctly to the cell surface when overexpressed and to induce synaptic differentiation. (PMID:21278334)
• Five genes have been directly disrupted in Tourette Syndrome by independent genomic rearrangements and copy number variations with unique breakpoints. (PMID:22948383)
• Neuroligins are adhesion proteins that bind to beta-neurexin to form functional synapses. (PMID:23431752)
• Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population. (PMID:23468870)
• In vitro models show NLGN4X knockdown directly impacts neurodevelopmental process during the formation of neurons and their connections. (PMID:23710042)
• The present study explores, for the first time, the contribution of NLGN3 and NLGN4X genetic variants in Greek patients with autistic disorder. (PMID:23851596)
• Our data provided a further evidence for the involvement of NLGN3 and NLGN4X gene in the pathogenesis of autism in Chinese population. (PMID:24570023)
• Endogenous NLGN4X is intensely phosphorylated on T707 upon PKC stimulation in human neurons. (PMID:25675530)
• Noncoding polymorphisms on NLGN4X may be associated to autism suggesting the key role of NLGN4X in autism pathophysiology and in its male prevalence. (PMID:27782075)
• Our data suggest that these four previously described neuroligin mutations are not primary risk factors for autism. (PMID:28948087)
• Steady-state fluorescence and microscale thermophoresis experiments allowed the authors to confirm the binding of some of mycotoxins to acetylcholinesterase and X-linked neuroligin 4, two proteins involved in synapse activity and, particularly for the second protein, neuronal plasticity and development. (PMID:29123130)
• NLGN4X might represent novel biomarkers and therapeutic targets for breast cancer. Inhibition of NLGN4X may be a new target for the prevention and treatment of breast cancer (PMID:29244827)
• the effects of rs1421589 within NRXN1, rs4844285 and rs11795613 within NLGN3, as well as rs5961397 within NLGX4X on Hirschsprung’s disease phenotypes were also statistically significant. (PMID:29622757)
• Neuroligin-4 is primarily expressed in cerebral cortex and localized to excitatory synapses. Overexpression of NLGN4 in human embryonic stem cell-derived neurons resulted in an increase in excitatory synapse numbers but a remarkable decrease in synaptic strength. The syndromic autism mutation NLGN4-R704C elicited more excitatory synapses but with increased functional synaptic transmission via a postsynaptic mechanism. (PMID:31257103)
• A Cluster of Autism-Associated Variants on X-Linked NLGN4X Functionally Resemble NLGN4Y. (PMID:32243781)
• Autism-associated variants of neuroligin 4X impair synaptogenic activity by various molecular mechanisms. (PMID:32873342)
• An Autism-Associated Mutation Impairs Neuroligin-4 Glycosylation and Enhances Excitatory Synaptic Transmission in Human Neurons. (PMID:33268543)
• Pathogenic paternally inherited NLGN4X deletion in a female with autism spectrum disorder: Clinical, cytogenetic, and molecular characterization. (PMID:33369065)
• RNA sequencing and functional studies of patient-derived cells reveal that neurexin-1 and regulators of this pathway are associated with poor outcomes in Ewing sarcoma. (PMID:34403115)
• The distribution of neuroligin4, an autism-related postsynaptic molecule, in the human brain. (PMID:36747195)
• Late stage melanoma is hallmarked by low NLGN4X expression leading to HIF1A accumulation. (PMID:38902533)

Cross-species orthologs

45 orthologs

Organism	Symbol	Gene ID
danio_rerio	nlgn4xb	ENSDARG00000077761
danio_rerio	nlgn4xa	ENSDARG00000079455
mus_musculus	Nlgn4l	ENSMUSG00000121607
drosophila_melanogaster	Est-6	FBGN0000592
drosophila_melanogaster	Est-P	FBGN0000594
drosophila_melanogaster	Glt	FBGN0001114
drosophila_melanogaster	Jhe	FBGN0010052
drosophila_melanogaster	alpha-Est1	FBGN0015568
drosophila_melanogaster	alpha-Est10	FBGN0015569
drosophila_melanogaster	alpha-Est2	FBGN0015570
drosophila_melanogaster	alpha-Est3	FBGN0015571
drosophila_melanogaster	alpha-Est4	FBGN0015572
drosophila_melanogaster	alpha-Est6	FBGN0015574
drosophila_melanogaster	alpha-Est7	FBGN0015575
drosophila_melanogaster	alpha-Est8	FBGN0015576
drosophila_melanogaster	alpha-Est9	FBGN0015577
drosophila_melanogaster	CG4757	FBGN0027584
drosophila_melanogaster	CG9287	FBGN0032057
drosophila_melanogaster	CG9289	FBGN0032058
drosophila_melanogaster	CG3841	FBGN0032131
drosophila_melanogaster	CG4382	FBGN0032132
drosophila_melanogaster	Jhedup	FBGN0034076
drosophila_melanogaster	gas	FBGN0034736
drosophila_melanogaster	alpha-Est5	FBGN0261393
caenorhabditis_elegans		WBGENE00000037
caenorhabditis_elegans		WBGENE00000038
caenorhabditis_elegans		WBGENE00007691
caenorhabditis_elegans		WBGENE00007692
caenorhabditis_elegans		WBGENE00007693
caenorhabditis_elegans		WBGENE00007695
caenorhabditis_elegans		WBGENE00008451
caenorhabditis_elegans		WBGENE00011362
caenorhabditis_elegans		WBGENE00011364
caenorhabditis_elegans		WBGENE00013873
caenorhabditis_elegans		WBGENE00013874
caenorhabditis_elegans		WBGENE00013875
caenorhabditis_elegans		WBGENE00015067
caenorhabditis_elegans		WBGENE00015071
caenorhabditis_elegans		WBGENE00015279
caenorhabditis_elegans		WBGENE00015284
caenorhabditis_elegans		WBGENE00016595
caenorhabditis_elegans		WBGENE00016862
caenorhabditis_elegans		WBGENE00016863
caenorhabditis_elegans	cest-27	WBGENE00018958
caenorhabditis_elegans		WBGENE00020688

Paralogs (13): TG (ENSG00000042832), ACHE (ENSG00000087085), BCHE (ENSG00000114200), CES5A (ENSG00000159398), NLGN4Y (ENSG00000165246), NLGN1 (ENSG00000169760), NLGN2 (ENSG00000169992), CEL (ENSG00000170835), CES4A (ENSG00000172824), CES3 (ENSG00000172828), CES2 (ENSG00000172831), NLGN3 (ENSG00000196338), CES1 (ENSG00000198848)

Protein

Protein identifiers

Neuroligin-4, X-linked — Q8N0W4 (reviewed: Q8N0W4)

Alternative names: HNLX

All UniProt accessions (3): Q8N0W4, A0A2R8Y6F7, A0A2R8YCI5

UniProt curated annotations — full annotation on UniProt →

Function. Cell surface protein involved in cell-cell-interactions via its interactions with neurexin family members.

Subunit / interactions. Homodimer. Interacts with NRXN1 in a calcium-dependent manner. Interaction with neurexins is mediated by heparan sulfate glycan modification on neurexin. Interacts through its C-terminus with DLG4/PSD-95 third PDZ domain.

Subcellular location. Cell membrane. Postsynaptic density membrane. Cell projection. Dendritic spine. Dendrite. Synapse.

Tissue specificity. Expressed at highest levels in heart. Expressed at lower levels in liver, skeletal muscle and pancreas and at very low levels in brain.

Post-translational modifications. N-glycosylated, contains high-mannose, hybrid, complex and sialylated N-glycans. N-glycosylation is essential for localization to synapses, dendrites, and the cell membrane, and enhances its availability for trans-synaptic adhesion. O-glycosylated.

Disease relevance. Autism, X-linked 2 (AUTSX2) [MIM:300495] A complex multifactorial, pervasive developmental disorder characterized by impairments in reciprocal social interaction and communication, restricted and stereotyped patterns of interests and activities, and the presence of developmental abnormalities by 3 years of age. Most individuals with autism also manifest moderate intellectual disability. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the type-B carboxylesterase/lipase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8N0W4-1	1	yes
Q8N0W4-2	2

RefSeq proteins (4): NP_001269074, NP_001269075, NP_065793, NP_851849* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000460	Nlgn	Family
IPR002018	CarbesteraseB	Domain
IPR019819	Carboxylesterase_B_CS	Conserved_site
IPR029058	AB_hydrolase_fold	Homologous_superfamily
IPR051093	Neuroligin/BSAL	Family

Pfam: PF00135

UniProt features (73 total): helix 26, strand 20, turn 8, disulfide bond 3, glycosylation site 2, mutagenesis site 2, topological domain 2, region of interest 2, signal peptide 1, chain 1, splice variant 1, sequence variant 1, sequence conflict 1, transmembrane region 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3BE8	X-RAY DIFFRACTION	2.2
2XB6	X-RAY DIFFRACTION	2.6
2WQZ	X-RAY DIFFRACTION	3.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N0W4-F1	78.99	0.60

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 712

Disulfide bonds (3): 110–146, 306–317, 476–510

Glycosylation sites (2): 511, 102

Mutagenesis-validated functional residues (2):

Position	Phenotype
102	n-glycosylation, localization to synapses, dendrites, and the cell membrane, as well as availability for trans-synaptic
511	n-glycosylation, localization to synapses, dendrites, and the cell membrane, as well as availability for trans-synaptic

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6794361	Neurexins and neuroligins

MSigDB gene sets: 155 (showing top): GOBP_HINDBRAIN_DEVELOPMENT, GOBP_METENCEPHALON_DEVELOPMENT, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_SYNAPSE_ASSEMBLY, GOBP_MEMBRANE_BIOGENESIS, GOBP_ADULT_BEHAVIOR, GOBP_GROWTH, GOCC_CELL_SURFACE, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_CELL_CELL_SIGNALING, GOBP_CELL_CELL_ADHESION, GOBP_CELL_JUNCTION_ORGANIZATION

GO Biological Process (18): brainstem development (GO:0003360), neuron cell-cell adhesion (GO:0007158), synapse assembly (GO:0007416), learning (GO:0007612), cerebellum development (GO:0021549), neuron differentiation (GO:0030182), adult behavior (GO:0030534), social behavior (GO:0035176), organ growth (GO:0035265), cell-cell junction organization (GO:0045216), modulation of chemical synaptic transmission (GO:0050804), synapse organization (GO:0050808), regulation of synapse assembly (GO:0051963), vocalization behavior (GO:0071625), negative regulation of excitatory postsynaptic potential (GO:0090394), presynaptic membrane assembly (GO:0097105), presynapse assembly (GO:0099054), cell adhesion (GO:0007155)

GO Molecular Function (7): chloride ion binding (GO:0031404), neurexin family protein binding (GO:0042043), protein homodimerization activity (GO:0042803), cell adhesion molecule binding (GO:0050839), scaffold protein binding (GO:0097110), cell adhesion mediator activity (GO:0098631), protein binding (GO:0005515)

GO Cellular Component (14): plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020), dendrite (GO:0030425), synapse (GO:0045202), excitatory synapse (GO:0060076), postsynaptic density membrane (GO:0098839), glutamatergic synapse (GO:0098978), GABA-ergic synapse (GO:0098982), symmetric, GABA-ergic, inhibitory synapse (GO:0098983), asymmetric, glutamatergic, excitatory synapse (GO:0098985), postsynaptic specialization membrane (GO:0099634), postsynaptic membrane (GO:0045211), neuron to neuron synapse (GO:0098984)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Protein-protein interactions at synapses	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
synapse	4
behavior	3
anatomical structure development	2
cell junction organization	2
synapse assembly	2
protein binding	2
cellular anatomical structure	2
postsynaptic membrane	2
synaptic membrane	2
cell-cell adhesion	1
nervous system development	1
cell junction assembly	1
synapse organization	1
learning or memory	1
metencephalon development	1
cell differentiation	1
generation of neurons	1
biological process involved in intraspecies interaction between organisms	1
multicellular organismal process	1
developmental growth	1
chemical synaptic transmission	1
regulation of trans-synaptic signaling	1
regulation of synapse organization	1
regulation of cell junction assembly	1
negative regulation of biological process	1
excitatory postsynaptic potential	1
modulation of excitatory postsynaptic potential	1
membrane assembly	1
presynaptic membrane organization	1
presynapse assembly	1
cellular component assembly	1
presynapse organization	1
cellular process	1
anion binding	1
signaling receptor binding	1
identical protein binding	1
protein dimerization activity	1
cell adhesion	1
cell adhesion molecule binding	1
binding	1

Protein interactions and networks

STRING

1700 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NLGN4X	NRXN1	Q9ULB1	999
NLGN4X	NRXN2	Q9P2S2	998
NLGN4X	SHANK3	Q9BYB0	992
NLGN4X	DLG4	P78352	987
NLGN4X	SHANK2	Q9UPX8	929
NLGN4X	CNTNAP2	Q9UHC6	852
NLGN4X	PTCHD1	Q96NR3	804
NLGN4X	SHANK1	Q9Y566	776
NLGN4X	FMR1	Q06787	771
NLGN4X	GPHN	Q9NQX3	768
NLGN4X	CNTN4	Q8IWV2	767
NLGN4X	CDH9	Q9ULB4	762
NLGN4X	CDH10	Q9Y6N8	739
NLGN4X	MAGI2	Q86UL8	731
NLGN4X	MECP2	P51608	724

IntAct

117 interactions, top by confidence:

A	B	Type	Score
BRK1	CYFIP1	psi-mi:“MI:0914”(association)	0.640
NLGN4X	Nrxn1	psi-mi:“MI:0407”(direct interaction)	0.560
Nrxn1	NLGN4X	psi-mi:“MI:0407”(direct interaction)	0.560
NLGN4X	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.440
SNX27	NLGN4X	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN4X	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
MAGI2	NLGN4X	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN4X	SHANK1	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN4X	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN4X	DLG2	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN4X	GOPC	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN4X	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN4X	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440
TAMALIN	NLGN4X	psi-mi:“MI:0407”(direct interaction)	0.440
PDZD7	NLGN4X	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN4X	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN4X	SNTB1	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN4X	PICK1	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN4X	DLG1	psi-mi:“MI:0407”(direct interaction)	0.440
MAGI1	NLGN4X	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN4X	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN4X	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN4X	SNTA1	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN4X	HTRA4	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN4X	TJP2	psi-mi:“MI:0407”(direct interaction)	0.440
NLGN4X	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (6): NLGN4X (Affinity Capture-MS), NLGN4X (Proximity Label-MS), DLG4 (Affinity Capture-Western), NLGN4X (Affinity Capture-MS), NLGN4X (Affinity Capture-MS), NLGN4X (Positive Genetic)

ESM2 similar proteins: A0A0G2JXT6, A0A6I8TCE0, A2ALK8, A4IFG2, A9JRL3, B0X4T2, O42127, O82656, P11362, P16092, P18052, P18433, P18460, P18461, P21802, P21803, P21804, P22182, P22607, P26045, P28191, P29074, P35832, P36583, Q03364, Q04589, Q16832, Q21029, Q24488, Q4R6N0, Q504C1, Q5R4L1, Q61851, Q62371, Q62688, Q6DD21, Q8JG38, Q8N0W4, Q90330, Q90413

Diamond homologs: A0A060S684, A0A0E4AET8, A0A443HK52, D4ASH1, D4AZ78, D4B1N9, I1RDA9, I6Y9F7, O08710, O16168, O16169, O16170, O16171, O16172, O46421, O62760, O62761, P01266, P01267, P04058, P06882, P07692, P08171, P10959, P12337, P12992, P16303, P16854, P17573, P18142, P20261, P21836, P21837, P21927, P22394, P23795, P25725, P25726, P30122, P32749

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
NLGN4X	“up-regulates activity”	NRXN1	binding
NLGN4X	“up-regulates activity”	NRXN2	binding
NLGN4X	“up-regulates activity”	NRXN3	binding
NLGN4X	“up-regulates activity”	DLG4	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 81 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ras activation upon Ca2+ influx through NMDA receptor	5	52.9×	2e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	50.4×	2e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	50.4×	2e-06
Long-term potentiation	5	44.1×	2e-06
Assembly and cell surface presentation of NMDA receptors	9	42.3×	5e-11
Neurexins and neuroligins	11	40.1×	4e-13
Protein-protein interactions at synapses	6	29.5×	2e-06
RHO GTPase cycle	6	6.7×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	76.5×	2e-14
protein localization to synapse	6	60.5×	8e-08
receptor clustering	7	57.5×	6e-09
regulation of postsynaptic membrane neurotransmitter receptor levels	6	39.1×	7e-07
cell-cell adhesion	10	13.4×	4e-07
protein-containing complex assembly	8	12.0×	2e-05
chemical synaptic transmission	8	8.1×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

390 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	7
Uncertain significance	233
Likely benign	57
Benign	18

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
1304111	NM_181332.3(NLGN4X):c.1075C>T (p.Gln359Ter)	Pathogenic
148410	GRCh38/hg38 Xp22.32(chrX:5885166-5914976)x0	Pathogenic
152258	GRCh38/hg38 Xp22.32-22.31(chrX:5982467-6100650)x0	Pathogenic
1730501	NM_181332.3(NLGN4X):c.334dup (p.Gln112fs)	Pathogenic
2577594	NM_181332.3(NLGN4X):c.259C>T (p.Arg87Trp)	Pathogenic
3062584	GRCh37/hg19 Xp22.32-22.31(chrX:5872585-6127713)	Pathogenic
374392	NM_181332.3(NLGN4X):c.301C>T (p.Arg101Ter)	Pathogenic
441968	GRCh37/hg19 Xp22.33-11.21(chrX:168564-57413442)x1	Pathogenic
4531342	NM_181332.3(NLGN4X):c.779_782dup (p.Leu262fs)	Pathogenic
521221	NM_181332.3(NLGN4X):c.1747C>T (p.Arg583Trp)	Pathogenic
1303850	NM_181332.3(NLGN4X):c.625+1G>A	Likely pathogenic
2500874	NM_181332.3(NLGN4X):c.626-1G>A	Likely pathogenic
3062546	GRCh37/hg19 Xp22.32(chrX:5746197-5814098)	Likely pathogenic
4683013	GRCh37/hg19 Xp22.32-22.31(chrX:4793094-6176750)x0	Likely pathogenic
564748	GRCh37/hg19 Xp22.33-22.31(chrX:3649821-6645906)x0	Likely pathogenic
816289	GRCh37/hg19 Xp22.32-22.31(chrX:5871585-6074724)x0	Likely pathogenic
816290	GRCh37/hg19 Xp22.32(chrX:5912902-5994585)x1	Likely pathogenic

SpliceAI

3334 predictions. Top by Δscore:

Variant	Effect	Δscore
X:5893662:GATCA:G	acceptor_gain	1.0000
X:5893664:TCA:T	acceptor_gain	1.0000
X:5893665:CA:C	acceptor_gain	1.0000
X:5893665:CAC:C	acceptor_gain	1.0000
X:5893665:CACTG:C	acceptor_loss	1.0000
X:5893667:C:CA	acceptor_loss	1.0000
X:5893667:C:CC	acceptor_gain	1.0000
X:5903075:AC:A	donor_gain	1.0000
X:5903076:CC:C	donor_gain	1.0000
X:5909238:CC:C	acceptor_gain	1.0000
X:5909239:CC:C	acceptor_gain	1.0000
X:5986857:TGC:T	donor_gain	1.0000
X:6029275:CTTA:C	donor_loss	1.0000
X:6029276:TTA:T	donor_loss	1.0000
X:6029277:TAC:T	donor_loss	1.0000
X:6029278:A:AC	donor_gain	1.0000
X:6029278:AC:A	donor_gain	1.0000
X:6029279:C:CT	donor_gain	1.0000
X:6029279:CC:C	donor_gain	1.0000
X:6029279:CCT:C	donor_gain	1.0000
X:6029279:CCTA:C	donor_gain	1.0000
X:6029428:AATAT:A	acceptor_gain	1.0000
X:6029429:ATAT:A	acceptor_gain	1.0000
X:6029429:ATATC:A	acceptor_gain	1.0000
X:6029430:TAT:T	acceptor_gain	1.0000
X:6029430:TATCT:T	acceptor_gain	1.0000
X:6029431:AT:A	acceptor_gain	1.0000
X:6029431:ATCTG:A	acceptor_gain	1.0000
X:6029432:TCT:T	acceptor_gain	1.0000
X:6029433:C:CC	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000011807 (X:5971125 A>G), RS1000015577 (X:6075118 C>G), RS1000021431 (X:6147207 A>T), RS1000025359 (X:6134673 A>G), RS1000032973 (X:6190806 C>G), RS1000038597 (X:6078935 C>T), RS1000088613 (X:5905826 C>A,T), RS1000093093 (X:6136070 C>G,T), RS1000093829 (X:5988349 G>A), RS1000126658 (X:6017745 G>A), RS1000135710 (X:6028584 G>A), RS1000138242 (X:6211524 G>C,T), RS1000152326 (X:6035004 G>A), RS1000156009 (X:6198029 A>G), RS1000187315 (X:6087212 T>A,C)

Disease associations

OMIM: gene MIM:300427 | disease phenotypes: MIM:300495, MIM:300497

GenCC curated gene-disease

Disease	Classification	Inheritance
autism, susceptibility to, X-linked 2	Strong	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
X-linked complex neurodevelopmental disorder	Definitive	XL

Mondo (6): autism, susceptibility to, X-linked 2 (MONDO:0010341), X-linked intellectual disability (MONDO:0100284), Asperger syndrome, X-linked, susceptibility to, 2 (MONDO:0010343), autism spectrum disorder (MONDO:0005258), X-linked complex neurodevelopmental disorder (MONDO:0100148), intellectual disability (MONDO:0001071)

Orphanet (2): NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

20 total (20 of 20 shown, HPO-id order):

HPO	Term
HP:0000717	Autism
HP:0000721	Lack of spontaneous play
HP:0000723	Restrictive behavior
HP:0000728	Reduced ability to form peer relationships
HP:0000729	Autistic behavior
HP:0000732	Inflexible adherence to routines
HP:0000733	Motor stereotypy
HP:0000750	Delayed speech and language development
HP:0000758	Abnormal nonverbal communicative behavior
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001256	Mild intellectual disability
HP:0001357	Plagiocephaly
HP:0001417	X-linked inheritance
HP:0001426	Non-Mendelian inheritance
HP:0002332	Lack of peer relationships
HP:0002353	EEG abnormality
HP:0003144	Increased serum serotonin
HP:0003745	Sporadic
HP:0011463	Childhood onset

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002539_96	Schizophrenia	2.000000e-08
GCST006803_59	Schizophrenia	2.000000e-10
GCST009391_786	Metabolite levels	2.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010395	sphingomyelin 22:0 measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D038901	X-Linked Intellectual Disability	C10.597.606.360.455; C16.320.322.500; C16.320.400.525

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, affects methylation, increases expression	2
Progesterone	increases expression	2
Valproic Acid	decreases expression, decreases methylation	2
titanium dioxide	decreases expression	1
sodium arsenite	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Temozolomide	increases expression	1
Zoledronic Acid	increases expression	1
Cadmium	decreases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Silver	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Aflatoxin B1	decreases methylation	1
Medroxyprogesterone Acetate	increases expression	1
Okadaic Acid	decreases expression	1
Acrylamide	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1YM	Abcam HeLa NLGN4X KO	Cancer cell line	Female
CVCL_E0YM	Ubigene MDA-MB-231 NLGN4X KO	Cancer cell line	Female

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD
NCT06229210	PHASE3	RECRUITING	Safety and Tolerability Trial of Lumateperone in Pediatric Patients With Schizophrenia, Bipolar Disorder or Autism Spectrum Disorder