Human Gene Module / Chromosome X / NLGN4X

NLGN4Xneuroligin 4, X-linked

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
18 / 30
Rare Variants / Common Variants
30 / 12
Aliases
NLGN4X, HLNX,  HNLX,  NLGN,  NLGN4,  ASPGX2,  AUTSX2,  KIAA1260,  MGC22376
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Genetic Association
Chromosome Band
Xp22.32-p22.31
Associated Disorders
ASD, ADHD
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 .

Reports related to NLGN4X (30 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Jamain S , et al. (2003) Yes -
2 Highly Cited X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. Laumonnier F , et al. (2004) No ASD
3 Negative Association Mutation screening of X-chromosomal neuroligin genes: no mutations in 196 autism probands. Vincent JB , et al. (2004) Yes -
4 Negative Association NLGN3/NLGN4 gene mutations are not responsible for autism in the Quebec population. Gauthier J , et al. (2004) Yes -
5 Support Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients. Yan J , et al. (2004) Yes -
6 Positive Association Analysis of four neuroligin genes as candidates for autism. Ylisaukko-oja T , et al. (2005) Yes -
7 Negative Association Absence of coding mutations in the X-linked genes neuroligin 3 and neuroligin 4 in individuals with autism from the IMGSAC collection. Blasi F , et al. (2006) Yes -
8 Recent Recommendation Structure function and splice site analysis of the synaptogenic activity of the neurexin-1 beta LNS domain. Graf ER , et al. (2006) No -
9 Recent Recommendation Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism. Jamain S , et al. (2008) No -
10 Support Familial deletion within NLGN4 associated with autism and Tourette syndrome. Lawson-Yuen A , et al. (2008) Yes TS
11 Recent Recommendation Unusually rapid evolution of Neuroligin-4 in mice. Bolliger MF , et al. (2008) No -
12 Support Autism and nonsyndromic mental retardation associated with a de novo mutation in the NLGN4X gene promoter causing an increased expression level. Daoud H , et al. (2009) Yes MR
13 Positive Association Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger syndrome. Chakrabarti B , et al. (2009) Yes -
14 Positive Association A substitution involving the NLGN4 gene associated with autistic behavior in the Greek population. Pampanos A , et al. (2009) Yes -
15 Recent Recommendation A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export. Zhang C , et al. (2009) No -
16 Support Interpretation of clinical relevance of X-chromosome copy number variations identified in a large cohort of individuals with cognitive disorders an... Willemsen MH , et al. (2012) No ASD, ADHD
17 Support Identification of Four Novel Synonymous Substitutions in the X-Linked Genes Neuroligin 3 and Neuroligin 4X in Japanese Patients with Autistic Spect... Yanagi K , et al. (2012) Yes -
18 Support Identification of rare X-linked neuroligin variants by massively parallel sequencing in males with autism spectrum disorder. Steinberg KM , et al. (2012) Yes -
19 Support A discovery resource of rare copy number variations in individuals with autism spectrum disorder. Prasad A , et al. (2013) Yes -
20 Support Using whole-exome sequencing to identify inherited causes of autism. Yu TW , et al. (2013) Yes -
21 Recent Recommendation The functional genetic link of NLGN4X knockdown and neurodevelopment in neural stem cells. Shi L , et al. (2013) No -
22 Positive Association Variations analysis of NLGN3 and NLGN4X gene in Chinese autism patients. Xu X , et al. (2014) Yes -
23 Recent Recommendation Integrated systems analysis reveals a molecular network underlying autism spectrum disorders. Li J , et al. (2015) Yes -
24 Recent Recommendation Autism-associated mutation inhibits protein kinase C-mediated neuroligin-4X enhancement of excitatory synapses. Bemben MA , et al. (2015) No -
25 Recent Recommendation Pathogenic mechanism of an autism-associated neuroligin mutation involves altered AMPA-receptor trafficking. Chanda S , et al. (2015) No -
26 Support GABA/Glutamate synaptic pathways targeted by integrative genomic and electrophysiological explorations distinguish autism from intellectual disabil... Bonnet-Brilhault F , et al. (2015) Yes -
27 Support High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing. Martnez F , et al. (2016) No Autistic behavior
28 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
29 Positive Association Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Pardias AF , et al. (2018) No -
30 Support De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis. Wang S , et al. (2018) No -
Rare Variants   (30)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain Unknown - Unknown 23275889 Prasad A , et al. (2013)
c.1310C>T p.(=) synonymous_variant - - - 15274046 Vincent JB , et al. (2004)
c.1397C>T p.(=) synonymous_variant - - - 15274046 Vincent JB , et al. (2004)
c.1805C>T p.(=) synonymous_variant - - - 15274046 Vincent JB , et al. (2004)
c.1186insT stop 396 frameshift_variant - - - 12669065 Jamain S , et al. (2003)
- - copy_number_gain Familial Maternal - 22796527 Willemsen MH , et al. (2012)
C2241TC2243G p.(=) synonymous_variant - - - 15274046 Vincent JB , et al. (2004)
c.-335G>A - 2KB_upstream_variant De novo - Simplex 19545860 Daoud H , et al. (2009)
c.484C>A p.Gln162Lys missense_variant De novo - Simplex 24570023 Xu X , et al. (2014)
c.392A>G p.Asn131Ser missense_variant Unknown - Unknown 25549968 Li J , et al. (2015)
c.297C>T p.(=) synonymous_variant Unknown - Unknown 22934180 Yanagi K , et al. (2012)
c.516C>T p.(=) synonymous_variant Unknown - Unknown 22934180 Yanagi K , et al. (2012)
c.1590C>T p.(=) synonymous_variant Unknown - Unknown 22934180 Yanagi K , et al. (2012)
c.1564G>A p.Val522Met missense_variant De novo - Simplex 30257206 Wang S , et al. (2018)
c.985C>T p.Gln329Ter stop_gained Familial Maternal Simplex 23352163 Yu TW , et al. (2013)
A>G - 3_prime_UTR_variant Familial Maternal Multiplex 23020841 Steinberg KM , et al. (2012)
c.250G>A p.Gly84Arg missense_variant Familial Maternal Simplex 24570023 Xu X , et al. (2014)
c.632delT p.Leu211Ter frameshift_variant Unknown - Simplex 28263302 C Yuen RK , et al. (2017)
c.847G>A p.Ala283Thr missense_variant Familial Maternal Simplex 24570023 Xu X , et al. (2014)
c.820C>T p.Gln274Ter stop_gained Familial Maternal Simplex 28263302 C Yuen RK , et al. (2017)
c.1133A>G p.Lys378Arg missense_variant Familial Maternal - 19645625 Pampanos A , et al. (2009)
del(2) - 3_prime_UTR_variant Familial Maternal Multiplex 23020841 Steinberg KM , et al. (2012)
- - copy_number_loss Familial Maternal Multi-generational 18231125 Lawson-Yuen A , et al. (2008)
c.1133A>G p.Lys378Arg missense_variant Familial Maternal Simplex 15622415 Yan J , et al. (2004)
c.2297G>A p.Arg766Gln missense_variant Familial Maternal Simplex 23352163 Yu TW , et al. (2013)
c.1207G>A p.Val403Met missense_variant Familial Maternal Multiplex 15622415 Yan J , et al. (2004)
c.2110C>T p.Arg704Cys missense_variant Familial Maternal Multiplex 15622415 Yan J , et al. (2004)
c.295G>A p.Gly99Ser missense_variant Familial Maternal Multi-generational 15622415 Yan J , et al. (2004)
c.1361_1372delTGGCCACCGCCG p.Val454_Ala457del inframe_deletion De novo - - 27620904 Martnez F , et al. (2016)
c.1253_1254delAG p.Glu418AspfsTer12 frameshift_variant Familial Maternal Multi-generational 14963808 Laumonnier F , et al. (2004)
Common Variants   (12)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.1777C>T;c.1837C>T p.Leu593Phe;p.Leu613Phe missense_variant - - - 16508939 Blasi F , et al. (2006)
c.1777C>T;c.1837C>T p.Leu593Phe;p.Leu613Phe missense_variant - - - 15389766 Gauthier J , et al. (2004)
c.-306+6390T>C;c.-305-29322T>C;c.-306+5679T>C - intron_variant - - - 19598235 Chakrabarti B , et al. (2009)
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 intron_variant, 2KB_upstream_variant - - - 16508939 Blasi F , et al. (2006)
c.-613+727G>C;c.-1240G>C;c.-431G>C;c.-306+727G>C;c.-1485G>C;c.-1254G>C;c.-2163G>C G34C intron_variant, 2KB_upstream_variant, 5_prime_UTR_variant - - - 16508939 Blasi F , et al. (2006)
- - intron_variant, microsatellite - - - 16077734 Ylisaukko-oja T , et al. (2005)
c.1779C>G;c.1839C>G p.(=) synonymous_variant - - - 24570023 Xu X , et al. (2014)
c.1779C>G;c.1839C>G p.(=) synonymous_variant - - - 16508939 Blasi F , et al. (2006)
c.1779C>G;c.1839C>G p.(=) synonymous_variant - - - 15389766 Gauthier J , et al. (2004)
c.625+26439T>C;c.685+26439T>C - intron_variant - - - 29483656 Pardias AF , et al. (2018)
c.1397C>T;c.933C>T;c.993C>T p.(=) synonymous_variant - - - 16508939 Blasi F , et al. (2006)
c.1777C>T;c.1837C>T p.Leu593Phe;p.Leu613Phe missense_variant - - - 24570023 Xu X , et al. (2014)
SFARI Gene score
3

Suggestive Evidence

3

Score Delta: Increased from 3 to 4.4 + acc4

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

4/1/2017
3
icon
3

Increased from 3 to 3

Description

Several studies have observed rare variants in the NLGN4X gene with autism. In addition, 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). NLGN4X interacts with another ASD gene, NRXN1.

Reports Added
[Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism.2003] [Mutation screening of X-chromosomal neuroligin genes: no mutations in 196 autism probands.2004] [NLGN3/NLGN4 gene mutations are not responsible for autism in the Quebec population.2004] [Analysis of four neuroligin genes as candidates for autism.2005] [Absence of coding mutations in the X-linked genes neuroligin 3 and neuroligin 4 in individuals with autism from the IMGSAC collection.2006] [Familial deletion within NLGN4 associated with autism and Tourette syndrome.2008] [Autism and nonsyndromic mental retardation associated with a de novo mutation in the NLGN4X gene promoter causing an increased expression level.2009] [Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger syndrome.2009] [A substitution involving the NLGN4 gene associated with autistic behavior in the Greek population.2009] [Identification of Four Novel Synonymous Substitutions in the X-Linked Genes Neuroligin 3 and Neuroligin 4X in Japanese Patients with Autistic Spect...2012] [Identification of rare X-linked neuroligin variants by massively parallel sequencing in males with autism spectrum disorder.2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Using whole-exome sequencing to identify inherited causes of autism.2013] [Variations analysis of NLGN3 and NLGN4X gene in Chinese autism patients.2014] [Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.2015] [Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients.2004] [Interpretation of clinical relevance of X-chromosome copy number variations identified in a large cohort of individuals with cognitive disorders an...2012] [Structure function and splice site analysis of the synaptogenic activity of the neurexin-1 beta LNS domain.2006] [Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism.2008] [Unusually rapid evolution of Neuroligin-4 in mice.2008] [A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export.2009] [The functional genetic link of NLGN4X knockdown and neurodevelopment in neural stem cells.2013] [Autism-associated mutation inhibits protein kinase C-mediated neuroligin-4X enhancement of excitatory synapses.2015] [Pathogenic mechanism of an autism-associated neuroligin mutation involves altered AMPA-receptor trafficking.2015] [GABA/Glutamate synaptic pathways targeted by integrative genomic and electrophysiological explorations distinguish autism from intellectual disabil...2015] [X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family.2004] [High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing.2016] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.2017]
10/1/2016
3
icon
3

Increased from 3 to 3

Description

Several studies have observed rare variants in the NLGN4X gene with autism. In addition, 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). NLGN4X interacts with another ASD gene, NRXN1.

4/1/2015
3
icon
3

Increased from 3 to 3

Description

Several studies have observed rare variants in the NLGN4X gene with autism. In addition, 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). NLGN4X interacts with another ASD gene, NRXN1.

1/1/2015
3
icon
3

Increased from 3 to 3

Description

Several studies have observed rare variants in the NLGN4X gene with autism. In addition, 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). NLGN4X interacts with another ASD gene, NRXN1.

7/1/2014
No data
icon
3

Increased from No data to 3

Description

Several studies have observed rare variants in the NLGN4X gene with autism. In addition, 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). NLGN4X interacts with another ASD gene, NRXN1.

4/1/2014
No data
icon
3

Increased from No data to 3

Description

Several studies have observed rare variants in the NLGN4X gene with autism. In addition, 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). NLGN4X interacts with another ASD gene, NRXN1.

Krishnan Probability Score

Score 0.49662832886019

Ranking 2551/25841 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 0.93229855900972

Ranking 2901/18225 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
Sanders TADA Score

Score 0.94481636431511

Ranking 16224/18665 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 41

Ranking 46/461 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.
CNVs associated with NLGN4X(1 CNVs)
Xp22.32-p22.31 2 Deletion-Duplication 3  /  3
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