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Relevance to Autism

Several studies have found rare variants in the NLGN4X gene in autism. Association was seen in Finnish and Caucasian population cohorts. However, several studies have found no rare variants in the NLGN4X gene in autistic patients in their cohorts (including Quebec population and IMGSAC cohorts).

Molecular Function

Neuroligins are cell-adhesion molecules at the postsynaptic side of the synapse .

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism.
ASD
Positive Association
Variations analysis of NLGN3 and NLGN4X gene in Chinese autism patients.
ASD
Positive Association
A substitution involving the NLGN4 gene associated with autistic behavior in the Greek population.
ASD
Positive Association
Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger syndrome.
ASD
Positive Association
Analysis of four neuroligin genes as candidates for autism.
ASD
Positive Association
Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.
SCZ
Negative Association
Analysis of the SNP rs3747333 and rs3747334 in NLGN4X gene in autism spectrum disorder: a meta-analysis.
ASD
Negative Association
Not all neuroligin 3 and 4X missense variants lead to significant functional inactivation.
ASD
Negative Association
Absence of coding mutations in the X-linked genes neuroligin 3 and neuroligin 4 in individuals with autism from the IMGSAC collection.
ASD
Negative Association
NLGN3/NLGN4 gene mutations are not responsible for autism in the Quebec population.
ASD
Negative Association
Mutation screening of X-chromosomal neuroligin genes: no mutations in 196 autism probands.
ASD
Support
Identification of rare X-linked neuroligin variants by massively parallel sequencing in males with autism spectrum disorder.
ASD
Support
De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis.
TS
Support
Identification of Four Novel Synonymous Substitutions in the X-Linked Genes Neuroligin 3 and Neuroligin 4X in Japanese Patients with Autistic Spect...
ASD
Support
Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder
ASD
Support
Interpretation of clinical relevance of X-chromosome copy number variations identified in a large cohort of individuals with cognitive disorders an...
DD, ID
ASD, ADHD
Support
High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing.
ID
Autistic behavior
Support
Genome-wide rare variant score associates with morphological subtypes of autism spectrum disorder
ASD
ADHD, TS
Support
A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export.
ASD
Support
GABA/Glutamate synaptic pathways targeted by integrative genomic and electrophysiological explorations distinguish autism from intellectual disabil...
ASD, ID
Support
Integrating de novo and inherited variants in 42
ASD
Support
Autism and nonsyndromic mental retardation associated with a de novo mutation in the NLGN4X gene promoter causing an increased expression level.
ASD
MR
Support
ASD
ID
Support
Using whole-exome sequencing to identify inherited causes of autism.
ASD
Support
New Candidates for Autism/Intellectual Disability Identified by Whole-Exome Sequencing
DD, ID
Stereotypy
Support
Familial deletion within NLGN4 associated with autism and Tourette syndrome.
ASD
TS
Support
ID, epilepsy/seizures
Support
A discovery resource of rare copy number variations in individuals with autism spectrum disorder.
ASD
Support
Next-Generation Sequencing in Korean Children With Autism Spectrum Disorder and Comorbid Epilepsy
ASD
ID, epilepsy/seizures
Support
Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients.
ASD
Support
ASD
Highly Cited
X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family.
ID
ASD
Recent Recommendation
Unusually rapid evolution of Neuroligin-4 in mice.
Recent Recommendation
A Cluster of Autism-Associated Variants on X-Linked NLGN4X Functionally Resemble NLGN4Y
ASD, ID
Recent Recommendation
Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism.
Recent Recommendation
Neuroligin-4 Regulates Excitatory Synaptic Transmission in Human Neurons.
Recent Recommendation
Structure function and splice site analysis of the synaptogenic activity of the neurexin-1 beta LNS domain.
Recent Recommendation
Pathogenic mechanism of an autism-associated neuroligin mutation involves altered AMPA-receptor trafficking.
Recent Recommendation
Autism-associated mutation inhibits protein kinase C-mediated neuroligin-4X enhancement of excitatory synapses.
Recent Recommendation
Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.
ASD
Recent Recommendation
The functional genetic link of NLGN4X knockdown and neurodevelopment in neural stem cells.
Recent Recommendation
Autism-associated variants of neuroligin 4X impair synaptogenic activity by various molecular mechanisms
ASD

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN172R001 
 frameshift_variant 
 c.1186_1187insT 
 p.Asp396ValfsTer16 
 Familial 
 Maternal 
 Multiplex 
 GEN172R002 
 missense_variant 
 c.1133A>G 
 p.Lys378Arg 
 Familial 
 Maternal 
  
 GEN172R003 
 synonymous_variant 
 c.1397C>T 
 p.Pro466Leu 
  
  
  
 GEN172R004 
 synonymous_variant 
 c.1310G>A 
 p.Arg437Gln 
  
  
  
 GEN172R005 
 synonymous_variant 
 c.1805C>T 
 p.(=) 
  
  
  
 GEN172R006 
 synonymous_variant 
 C2241TC2243G 
 p.(=) 
  
  
  
 GEN172R007 
 2KB_upstream_variant 
 c.-335G>A 
  
 De novo 
  
 Simplex 
 GEN172R008 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Multiplex 
 GEN172R009 
 copy_number_gain 
  
  
 Familial 
 Maternal 
  
 GEN172R010 
 synonymous_variant 
 c.297C>T 
 p.Gly99= 
 Unknown 
  
 Unknown 
 GEN172R011 
 synonymous_variant 
 c.516C>T 
 p.Ile172= 
 Unknown 
  
 Unknown 
 GEN172R012 
 synonymous_variant 
 c.1590C>T 
 p.Phe530= 
 Unknown 
  
 Unknown 
 GEN172R013 
 3_prime_UTR_variant 
 c.1601+2982T>C 
  
 Familial 
 Maternal 
 Multiplex 
 GEN172R014 
 3_prime_UTR_variant 
 c.1601+969del 
  
 Familial 
 Maternal 
 Multiplex 
 GEN172R015 
 copy_number_gain 
  
  
 Unknown 
  
 Unknown 
 GEN172R016 
 stop_gained 
 c.985C>T 
 p.Gln329Ter 
 Familial 
 Maternal 
 Simplex 
 GEN172R017 
 missense_variant 
 c.2297G>A 
 p.Arg766Gln 
 Familial 
 Maternal 
 Simplex 
 GEN172R018 
 missense_variant 
 c.250G>A 
 p.Gly84Arg 
 Familial 
 Maternal 
 Simplex 
 GEN172R019 
 missense_variant 
 c.484C>A 
 p.Gln162Lys 
 De novo 
  
 Simplex 
 GEN172R020 
 missense_variant 
 c.847G>A 
 p.Ala283Thr 
 Familial 
 Maternal 
 Simplex 
 GEN172R021 
 missense_variant 
 c.392A>G 
 p.Asn131Ser 
 Unknown 
  
 Unknown 
 GEN172R022 
 missense_variant 
 c.295G>A 
 p.Gly99Ser 
 Familial 
 Maternal 
 Multiplex 
 GEN172R023 
 missense_variant 
 c.1133A>G 
 p.Lys378Arg 
 Familial 
 Maternal 
 Simplex 
 GEN172R024 
 missense_variant 
 c.1207G>A 
 p.Val403Met 
 Familial 
 Maternal 
 Multiplex 
 GEN172R025 
 missense_variant 
 c.2110C>T 
 p.Arg704Cys 
 Familial 
 Maternal 
 Multiplex 
 GEN172R026 
 frameshift_variant 
 c.1254_1255del 
 p.Glu418AspfsTer12 
 Familial 
 Maternal 
 Multi-generational 
 GEN172R027 
 inframe_deletion 
 c.1361_1372del 
 p.Val454_Ala457del 
 De novo 
  
  
 GEN172R028 
 stop_gained 
 c.820C>T 
 p.Gln274Ter 
 Familial 
 Maternal 
 Simplex 
 GEN172R029 
 frameshift_variant 
 c.632del 
 p.Leu211Ter 
 Unknown 
  
 Simplex 
 GEN172R030 
 missense_variant 
 c.1564G>A 
 p.Val522Met 
 De novo 
  
 Simplex 
 GEN172R031 
 missense_variant 
 c.259C>T 
 p.Arg87Trp 
 De novo 
  
 Multiplex 
 GEN172R032 
 missense_variant 
 c.281C>T 
 p.Pro94Leu 
 Unknown 
  
 Unknown 
 GEN172R033 
 missense_variant 
 c.302G>A 
 p.Arg101Gln 
 Familial 
 Maternal 
 Unknown 
 GEN172R034 
 missense_variant 
 c.325G>C 
 p.Val109Leu 
 Familial 
 Maternal 
 Unknown 
 GEN172R035 
 copy_number_loss 
  
  
 Unknown 
  
  
 GEN172R036 
 copy_number_loss 
  
  
 Unknown 
  
  
 GEN172R037 
 missense_variant 
 c.2167C>T 
 p.His723Tyr 
 De novo 
  
 Simplex 
 GEN172R038 
 splice_site_variant 
 c.1601+5G>A 
  
 De novo 
  
  
 GEN172R039 
 frameshift_variant 
 c.659del 
 p.Gly220AlafsTer29 
 Unknown 
  
  
 GEN172R040 
 inframe_indel 
 c.1581_1582delinsTT 
 p.Trp527_Thr528delinsCysSer 
 Familial 
 Maternal 
 Simplex 
 GEN172R041 
 missense_variant 
 c.1271A>C 
 p.Tyr424Ser 
 De novo 
  
  
 GEN172R042 
 missense_variant 
 c.295G>A 
 p.Gly99Ser 
 Familial 
 Maternal 
  
  et al.  
 GEN172R043 
 missense_variant 
 c.1360G>C 
 p.Val454Leu 
 Familial 
 Maternal 
 Multiplex 
  et al.  

Common

Variant ID
Polymorphism
SNP ID
Allele Change
Residue Change
Population Origin
Population Stage
Author, Year
 GEN172C001 
 intron_variant, microsatellite 
  
  
  
 Finnish 
 Discovery 
 GEN172C002 
 intron_variant 
 rs12836764 
 c.-306+6390T>C;c.-305-29322T>C;c.-306+5679T>C 
  
 Caucasian 
 Discovery 
 GEN172C003 
 missense_variant 
 rs3747333 
 c.1777C>T;c.1837C>T 
 p.Leu593Phe;p.Leu613Phe 
 Quebec 
 Discovery 
 GEN172C004 
 synonymous_variant 
 rs3747334 
 c.1779C>G;c.1839C>G 
 p.(=) 
 Quebec 
 Discovery 
 GEN172C005 
 intron_variant, 2KB_upstream_variant 
 rs2290487 
 c.-613+640G>A;c.-1327G>A;c.-518G>A;c.-306+640G>A;c.-1572G>A;c.-1341G>A;c.-2250G>A 
 G to A 
 IMGSAC 
 Discovery 
 GEN172C006 
 intron_variant, 2KB_upstream_variant, 5_prime_UTR_variant 
 rs2290488 
 c.-613+727G>C;c.-1240G>C;c.-431G>C;c.-306+727G>C;c.-1485G>C;c.-1254G>C;c.-2163G>C 
 G34C 
 IMGSAC 
 Discovery 
 GEN172C007 
 synonymous_variant 
 rs7049300 
 c.1397C>T;c.933C>T;c.993C>T 
 p.(=) 
 IMGSAC 
 Discovery 
 GEN172C008 
 missense_variant 
 rs3747333 
 c.1777C>T;c.1837C>T 
 p.Leu593Phe;p.Leu613Phe 
 IMGSAC 
 Discovery 
 GEN172C009 
 synonymous_variant 
 rs3747334 
 c.1779C>G;c.1839C>G 
 p.(=) 
 IMGSAC 
 Discovery 
 GEN172C010 
 missense_variant 
 rs3747333 
 c.1777C>T;c.1837C>T 
 p.Leu593Phe;p.Leu613Phe 
 318 Chinese ASD cases, 453 Chinese controls 
 Replication 
 GEN172C011 
 synonymous_variant 
 rs3747334 
 c.1779C>G;c.1839C>G 
 p.(=) 
 319 Chinese ASD cases, 453 Chinese controls 
 Replication 
 GEN172C012 
 intron_variant 
 rs12009217 
 c.625+26439T>C;c.685+26439T>C 
  
 40,675 SCZ cases and 64,643 controls (CLOZUK and independent PGC datasets) 
 Discovery 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
X
Deletion-Duplication
 45
 
X
Deletion-Duplication
 11
 
X
Duplication
 2
 
X
Deletion-Duplication
 3
 
X
Deletion
 2
 
X
Deletion
 4
 
X
Deletion-Duplication
 1
 
X
Deletion
 1
 
X
Duplication
 1
 
X
Duplication
 2
 
X
Deletion
 4
 
X
Deletion
 1
 
X
Duplication
 5
 
X
Deletion
 7
 
X
Duplication
 5
 
X
Deletion
 1
 
X
Deletion-Duplication
 21
 

Model Summary

Selective deficit in reciprocal social interaction and communication modeling ASD.

References

Type
Title
Author, Year
Primary
Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism.
Additional
Absence of deficits in social behaviors and ultrasonic vocalizations in later generations of mice lacking neuroligin4.
Additional

M_NLGN4X_1_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Gene trap vector inserted 340 bp downstream of the first exon. The resulting chimeric protein is nonfunctional, encoding residues 1138, in-frame with beta-galactosidase sequence.
Allele Type: Gene trapped
Strain of Origin: 129P2/OlaHsd
Genetic Background: B6.129P2
ES Cell Line: Not Specified
Mutant ES Cell Line: XST093
Model Source: BayGenomics

M_NLGN4X_2_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Gene trap insertion 340 bp downstream of the first exon of Nlgn4 creating a null mutation.
Allele Type: Targeted (Knock Out)
Strain of Origin: Not specified
Genetic Background: C57BL/6J
ES Cell Line: Not specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified

M_NLGN4X_3_KO_HT

Model Type: Genetic
Model Genotype: Heterozygous
Mutation: Gene trap insertion 340 bp downstream of the first exon of Nlgn4 creating a null mutation.
Allele Type: Targeted (Knock Out)
Strain of Origin: Not specified
Genetic Background: C57BL/6J
ES Cell Line: Not specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified

M_NLGN4X_1_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Brain size1
Decreased
Description: Reduced brain size
Exp Paradigm: Mri volumetry
 Magnetic resonance imaging (mri)
 3 months
Aggression1
Abnormal
Description: Abnormal aggression
Exp Paradigm: Resident intruder test
 Resident-intruder test
 3 months
Aggression1
Abnormal
Description: Abnormal aggression
Exp Paradigm: Modified resident intruder test
 Resident-intruder test
 3 months
Social interaction1
Decreased
Description: Reduced social interaction
Exp Paradigm: Direct contacts between genetically identical pairs test.
 Reciprocal social interaction test
 3 months
Social approach1
Abnormal
Description: Abnormal social approach.
Exp Paradigm: Social preference test in tripartite chamber.
 Three-chamber social approach test
 3 months
Ultrasonic vocalization1
Decreased
Description: Reduced ultrasonic vocalization
Exp Paradigm: Call latency towards unfamiliar female mouse in estrous.
 Monitoring ultrasonic vocalizations
 3 months
Mortality/lethality1
 No change
 Genotypic ratio of progeny from heterozygous parents
 3 months
Anxiety1
 No change
 Elevated plus maze test
 3 months
Anxiety1
 No change
 Open field test
 3 months
Exploratory activity1
 No change
 Object preference test
 3 months
Cognitive flexibility1
 No change
 Morris water maze test
 3 months
Cued or contextual fear conditioning: memory of cue1
 No change
 Fear conditioning test
 3 months
Spatial learning1
 No change
 Morris water maze test
 3 months
Motor coordination and balance1
 No change
 Accelerating rotarod test
 3 months
Seizures1
 No change
 NA
 3 months
Hearing1
 No change
 Startle response test
 3 months
Olfaction1
 No change
 Buried food test
 3 months
Sensorimotor gating1
 No change
 Prepulse inhibition
 3 months
Taste1
 No change
 Sucrose preference test
 3 months
Vision1
 No change
 Morris water maze test
 3 months
Social interaction1
 No change
 Hole-board test
 3 months
 Not Reported: Circadian sleep/wake cycle, Immune response, Maternal behavior, Molecular profile, Neurophysiology, Physiological parameters, Repetitive behavior

M_NLGN4X_2_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Ultrasonic vocalization1
 No change
 Monitoring ultrasonic vocalizations
 Unreported
Ultrasonic vocalization1
 No change
 Monitoring ultrasonic vocalizations
 Unreported
Ultrasonic vocalization1
 No change
 Monitoring ultrasonic vocalizations
 Unreported
Developmental trajectory1
 No change
 General observations
 P2-p14
Size/growth1
 No change
 General observations
 10-16 weeks
Size/growth1
 No change
 General observations
 Unreported
Anxiety2
 No change
 Open field test
 6-8 weeks
Anxiety1
 No change
 Elevated plus maze test
 Unreported
Object recognition memory1
 No change
 Reciprocal social interaction test
 3 weeks
General locomotor activity1
 No change
 Open field test
 Unreported
General locomotor activity: ambulatory activity2
 No change
 Open field test
 6-8 weeks
Motor coordination and balance1
 No change
 Accelerating rotarod test
 Unreported
Pain or nociception1
 No change
 Tail flick test
 Unreported
Pain or nociception1
 No change
 Hot plate test
 Unreported
Sensorimotor gating: tactile cue2
 No change
 Prepulse inhibition
 6-8 weeks
Startle response: tactile stimulus2
 No change
 Response to air puff
 6-8 weeks
Aggression1
 No change
 NA
 Unreported
Social interaction1
 No change
 Reciprocal social interaction test
 3 weeks
Social interaction1
 No change
 Reciprocal social interaction test
 Unreported
Social interaction1
 No change
 Three-chamber social approach test
 Unreported
Social interaction1
 No change
 Reciprocal social interaction test
 3 weeks
 Not Reported: Circadian sleep/wake cycle, Immune response, Maternal behavior, Molecular profile, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure

M_NLGN4X_3_KO_HT

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Ultrasonic vocalization1
 No change
 Monitoring ultrasonic vocalizations
 Unreported
Ultrasonic vocalization1
 No change
 Monitoring ultrasonic vocalizations
 Unreported
Ultrasonic vocalization1
 No change
 Monitoring ultrasonic vocalizations
 Unreported
Developmental trajectory1
 No change
 General observations
 P2-p14
Size/growth1
 No change
 General observations
 10-16 weeks
Size/growth1
 No change
 General observations
 Unreported
Anxiety2
 No change
 Open field test
 6-8 weeks
Anxiety1
 No change
 Elevated plus maze test
 Unreported
Object recognition memory1
 No change
 Reciprocal social interaction test
 3 weeks
General locomotor activity1
 No change
 Open field test
 Unreported
General locomotor activity: ambulatory activity2
 No change
 Open field test
 6-8 weeks
Motor coordination and balance1
 No change
 Accelerating rotarod test
 Unreported
Pain or nociception1
 No change
 Tail flick test
 Unreported
Pain or nociception1
 No change
 Hot plate test
 Unreported
Sensorimotor gating: tactile cue2
 No change
 Prepulse inhibition
 6-8 weeks
Startle response: tactile stimulus2
 No change
 Response to air puff
 6-8 weeks
Aggression1
 No change
 NA
 Unreported
Social interaction1
 No change
 Reciprocal social interaction test
 3 weeks
Social interaction1
 No change
 Reciprocal social interaction test
 Unreported
Social interaction1
 No change
 Three-chamber social approach test
 Unreported
Social interaction1
 No change
 Reciprocal social interaction test
 3 weeks
 Not Reported: Circadian sleep/wake cycle, Immune response, Maternal behavior, Molecular profile, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure





Download NLGN4X's Cytoscape file

Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
DLG4 DLG4discs, large homolog 4 (Drosophila) 1742 P78352 IP/WB
Bolliger MF , et al. 2001
FMR1 fragile X mental retardation 1 2332 G8JLE9 PAR-CLIP
Ascano M Jr , et al. 2012
NLGN3 neuroligin 3 54413 D3DVV1 IP; LC-MS/MS
Huttlin EL , et al. 2015
SCN2A sodium channel, voltage-gated, type II, alpha 1 24766 P04775 IP/WB
Bouzidi M , et al. 2002
SNTG2 syntrophin, gamma 2 54221 Q9NY99 Y2H; IP/WB
Yamakawa H , et al. 2007

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