Human Gene Module / Chromosome Y / NLGN4Y

NLGN4Yneuroligin 4, Y-linked

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
3 / 6
Rare Variants / Common Variants
10 / 0
Aliases
NLGN4Y, KIAA0951
Associated Syndromes
-
Chromosome Band
Yq11.221
Associated Disorders
ASD
Relevance to Autism

One study found no functional mutations in NLGN4Y in a Finnish population cohort and concluded that neuroligin mutations most probably represent rare causes of autism and that it is unlikely that the allelic variants in these genes would be major risk factors for autism (Ylisaukko-oja et al., 2005). Analysis of the coding sequences and splice junctions of the NLGN4Y gene in 335 male samples (290 with autism and 45 with intellectual disability) in Yan et al., 2008 identified a missense variant (p.Ile679Val) in a patient with autism, as well as his father with learning disabilities; this variant was not observed in 2986 control Y chromosomes. Ross et al., 2015 found that boys with 47,XYY syndrome (XYY) had increased risk of ASD behaviors on the social responsiveness scale (SRS) and increased attention deficits on the Conners' DSM-IV inattention and hyperactive scales; furthermore, peripheral expression of NLGN4Y in boys with XYY vs. typically developing controls was increased twofold in the XYY group, and results from the SRS total and autistic mannerisms scales, but not from the attention, anxiety or depression measures, correlated with peripheral expression of NLGN4Y in boys with XYY. Consistent with the hypothesis that increased NLGN4Y expression in XYY boys may contribute to ASD behaviors was the observation in Ross et al., 2019 that a male patient with the karyotype 46,X,idic(Y)(q11.22), which includes duplication of the Y short arm and proximal long arm and deletion of the distal long arm, had tall stature and cognitive function within the typical range, without autism features, as well as a two-fold increase in expression of Yp genes versus XY controls, and absent expression of deleted Yq genes, including NLGN4Y.

Molecular Function

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

External Links
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Human
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SFARI Genomic Platforms
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Reports related to NLGN4Y (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes Skaletsky H , et al. (2003) No -
2 Primary Analysis of four neuroligin genes as candidates for autism Ylisaukko-oja T , et al. (2005) Yes -
3 Support Analysis of the neuroligin 4Y gene in patients with autism Yan J , et al. (2008) Yes -
4 Recent Recommendation Behavioral phenotypes in males with XYY and possible role of increased NLGN4Y expression in autism features Ross JL , et al. (2015) No ASD or autistic behaviors
5 Support Y chromosome gene copy number and lack of autism phenotype in a male with an isodicentric Y chromosome and absent NLGN4Y expression Ross JL , et al. (2019) No -
6 Support - Hegde R et al. (2021) Yes -
Rare Variants   (10)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
C>A p.Asn163Lys missense_variant Unknown - - 35169779 Hegde R et al. (2021)
A>C p.Thr505= synonymous_variant Unknown - - 35169779 Hegde R et al. (2021)
C>T p.Phe513= synonymous_variant Unknown - - 35169779 Hegde R et al. (2021)
T>C p.Asn512= synonymous_variant Unknown - - 35169779 Hegde R et al. (2021)
c.1569G>C p.Val523= synonymous_variant Unknown - - 35169779 Hegde R et al. (2021)
c.1341T>C p.His447%3D synonymous_variant Unknown - - 35169779 Hegde R et al. (2021)
c.1470C>T p.Gly490%3D synonymous_variant Unknown - - 35169779 Hegde R et al. (2021)
c.1476A>G p.Glu492%3D synonymous_variant Unknown - - 35169779 Hegde R et al. (2021)
c.1560T>C p.Ser520%3D synonymous_variant Unknown - - 35169779 Hegde R et al. (2021)
c.2035A>G p.Ile679Val missense_variant Familial Paternal Simplex 18628683 Yan J , et al. (2008)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Analysis of the coding sequences and splice junctions of the NLGN4Y gene in 335 male samples (290 with autism and 45 with intellectual disability) in Yan et al., 2008 identified a missense variant (p.Ile679Val) in a patient with autism, as well as his father with learning disabilities; this variant was not observed in 2986 control Y chromosomes. An association study in a Finnish sample provided no support (entirely negative) (Ylisaukko-oja T et al., 2005), although distribution of Y chromosome haplotypes involving NLGN4Y polymorphisms was seen to be different between ASD cases and controls (p=0.0001 by 100,000 simulations) in Serajee and Mahbubul Huq, 2009. Ross et al., 2015 found that boys with 47,XYY syndrome (XYY) had increased risk of ASD behaviors on the social responsiveness scale (SRS) and increased attention deficits on the Conners' DSM-IV inattention and hyperactive scales; furthermore, peripheral expression of NLGN4Y in boys with XYY vs. typically developing controls was increased twofold in the XYY group, and results from the SRS total and autistic mannerisms scales, but not from the attention, anxiety or depression measures, correlated with peripheral expression of NLGN4Y in boys with XYY. Consistent with the hypothesis that increased NLGN4Y expression in XYY boys may contribute to ASD behaviors was the observation in Ross et al., 2019 that a male patient with the karyotype 46,X,idic(Y)(q11.22), which includes duplication of the Y short arm and proximal long arm and deletion of the distal long arm, had tall stature and cognitive function within the typical range, without autism features, as well as a two-fold increase in expression of Yp genes versus XY controls, and absent expression of deleted Yq genes, including NLGN4Y.

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Analysis of the coding sequences and splice junctions of the NLGN4Y gene in 335 male samples (290 with autism and 45 with intellectual disability) in Yan et al., 2008 identified a missense variant (p.Ile679Val) in a patient with autism, as well as his father with learning disabilities; this variant was not observed in 2986 control Y chromosomes. An association study in a Finnish sample provided no support (entirely negative) (Ylisaukko-oja T et al., 2005), although distribution of Y chromosome haplotypes involving NLGN4Y polymorphisms was seen to be different between ASD cases and controls (p=0.0001 by 100,000 simulations) in Serajee and Mahbubul Huq, 2009. Ross et al., 2015 found that boys with 47,XYY syndrome (XYY) had increased risk of ASD behaviors on the social responsiveness scale (SRS) and increased attention deficits on the Conners' DSM-IV inattention and hyperactive scales; furthermore, peripheral expression of NLGN4Y in boys with XYY vs. typically developing controls was increased twofold in the XYY group, and results from the SRS total and autistic mannerisms scales, but not from the attention, anxiety or depression measures, correlated with peripheral expression of NLGN4Y in boys with XYY. Consistent with the hypothesis that increased NLGN4Y expression in XYY boys may contribute to ASD behaviors was the observation in Ross et al., 2019 that a male patient with the karyotype 46,X,idic(Y)(q11.22), which includes duplication of the Y short arm and proximal long arm and deletion of the distal long arm, had tall stature and cognitive function within the typical range, without autism features, as well as a two-fold increase in expression of Yp genes versus XY controls, and absent expression of deleted Yq genes, including NLGN4Y.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Analysis of the coding sequences and splice junctions of the NLGN4Y gene in 335 male samples (290 with autism and 45 with intellectual disability) in Yan et al., 2008 identified a missense variant (p.Ile679Val) in a patient with autism, as well as his father with learning disabilities; this variant was not observed in 2986 control Y chromosomes. An association study in a Finnish sample provided no support (entirely negative) (Ylisaukko-oja T et al., 2005), although distribution of Y chromosome haplotypes involving NLGN4Y polymorphisms was seen to be different between ASD cases and controls (p=0.0001 by 100,000 simulations) in Serajee and Mahbubul Huq, 2009. Ross et al., 2015 found that boys with 47,XYY syndrome (XYY) had increased risk of ASD behaviors on the social responsiveness scale (SRS) and increased attention deficits on the Conners' DSM-IV inattention and hyperactive scales; furthermore, peripheral expression of NLGN4Y in boys with XYY vs. typically developing controls was increased twofold in the XYY group, and results from the SRS total and autistic mannerisms scales, but not from the attention, anxiety or depression measures, correlated with peripheral expression of NLGN4Y in boys with XYY. Consistent with the hypothesis that increased NLGN4Y expression in XYY boys may contribute to ASD behaviors was the observation in Ross et al., 2019 that a male patient with the karyotype 46,X,idic(Y)(q11.22), which includes duplication of the Y short arm and proximal long arm and deletion of the distal long arm, had tall stature and cognitive function within the typical range, without autism features, as well as a two-fold increase in expression of Yp genes versus XY controls, and absent expression of deleted Yq genes, including NLGN4Y.

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

Analysis of the coding sequences and splice junctions of the NLGN4Y gene in 335 male samples (290 with autism and 45 with intellectual disability) in Yan et al., 2008 identified a missense variant (p.Ile679Val) in a patient with autism, as well as his father with learning disabilities; this variant was not observed in 2986 control Y chromosomes. An association study in a Finnish sample provided no support (entirely negative) (Ylisaukko-oja T et al., 2005), although distribution of Y chromosome haplotypes involving NLGN4Y polymorphisms was seen to be different between ASD cases and controls (p=0.0001 by 100,000 simulations) in Serajee and Mahbubul Huq, 2009. Ross et al., 2015 found that boys with 47,XYY syndrome (XYY) had increased risk of ASD behaviors on the social responsiveness scale (SRS) and increased attention deficits on the Conners' DSM-IV inattention and hyperactive scales; furthermore, peripheral expression of NLGN4Y in boys with XYY vs. typically developing controls was increased twofold in the XYY group, and results from the SRS total and autistic mannerisms scales, but not from the attention, anxiety or depression measures, correlated with peripheral expression of NLGN4Y in boys with XYY. Consistent with the hypothesis that increased NLGN4Y expression in XYY boys may contribute to ASD behaviors was the observation in Ross et al., 2019 that a male patient with the karyotype 46,X,idic(Y)(q11.22), which includes duplication of the Y short arm and proximal long arm and deletion of the distal long arm, had tall stature and cognitive function within the typical range, without autism features, as well as a two-fold increase in expression of Yp genes versus XY controls, and absent expression of deleted Yq genes, including NLGN4Y.

Reports Added
[Analysis of the neuroligin 4Y gene in patients with autism.2008] [Y chromosome gene copy number and lack of autism phenotype in a male with an isodicentric Y chromosome and absent NLGN4Y expression.2019]
1/1/2015
4
icon
4

Decreased from 4 to 4

Description

Distribution of Y haplotypes was seen to be different between cases and controls (p=0.0001 by 100,000 simulations). Sequencing of 335 male samples identified rare missense variant at conserved position in 1 proband and father with intellectual disability, and this same variant was not seen in any of 2986 control Y chromsomes (~1500 boys). An association study in a Finnish sample provides no support (entirely negative) (Ylisaukko-oja T et al.).

Reports Added
[Behavioral phenotypes in males with XYY and possible role of increased NLGN4Y expression in autism features.2015]
7/1/2014
No data
icon
4

Increased from No data to 4

Description

Distribution of Y haplotypes was seen to be different between cases and controls (p=0.0001 by 100,000 simulations). Sequencing of 335 male samples identified rare missense variant at conserved position in 1 proband and father with intellectual disability, and this same variant was not seen in any of 2986 control Y chromsomes (~1500 boys). An association study in a Finnish sample provides no support (entirely negative) (Ylisaukko-oja T et al.).

4/1/2014
No data
icon
4

Increased from No data to 4

Description

Distribution of Y haplotypes was seen to be different between cases and controls (p=0.0001 by 100,000 simulations). Sequencing of 335 male samples identified rare missense variant at conserved position in 1 proband and father with intellectual disability, and this same variant was not seen in any of 2986 control Y chromsomes (~1500 boys). An association study in a Finnish sample provides no support (entirely negative) (Ylisaukko-oja T et al.).

Krishnan Probability Score

Score 0.49762798380121

Ranking 2355/25841 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.
Original Source
ExAC Score

Score 0.64554756688399

Ranking 4764/18225 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
Original Source
Sanders TADA Score

Score 0.93703147745644

Ranking 13390/18665 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).
Original Source
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