Human Gene Module / Chromosome 3 / CNTN4

CNTN4contactin 4

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
13 / 20
Rare Variants / Common Variants
16 / 4
Aliases
CNTN4, AXCAM,  BIG-2,  CNTN4A,  MGC33615,  CNTN4
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association
Chromosome Band
3p26.3-p26.2
Associated Disorders
DD/NDD, ID
Relevance to Autism

Several studies have found rare single gene variations in the CNTN4 gene in patients with ASD. These variations include deletions, missense mutations and a duplication. For example, a deletion in the CNTN4 gene was found in a patient with PDD-NOS and mild intellectual disability (Leblond et al., 2012). On the contrary, one study attempted to find a genetic association between CNTN4 variants and autism in a sample of CORA families but did not find any statistically significant results.

Molecular Function

This gene encodes a member of the contactin family of immunoglobulins. Contactins are axon-associated cell adhesion molecules that function in neuronal network formation and plasticity. The encoded protein is a glycosylphosphatidylinositol-anchored neuronal membrane protein that may play a role in the formation of axon connections in the developing nervous system.

Reports related to CNTN4 (20 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Disruption of contactin 4 (CNTN4) results in developmental delay and other features of 3p deletion syndrome. Fernandez T , et al. (2004) Yes DD, ID
2 Primary Disruption of contactin 4 in three subjects with autism spectrum disorder. Roohi J , et al. (2008) Yes -
3 Recent Recommendation BIG-2 mediates olfactory axon convergence to target glomeruli. Kaneko-Goto T , et al. (2008) No -
4 Support Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder. Christian SL , et al. (2008) Yes -
5 Recent Recommendation Disruption of Contactin 4 (CNTN4) results in developmental delay and other features of 3p deletion syndrome. Fernandez T , et al. (2008) No -
6 Positive Association Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Glessner JT , et al. (2009) Yes -
7 Recent Recommendation The protein tyrosine phosphatases PTPRZ and PTPRG bind to distinct members of the contactin family of neural recognition molecules. Bouyain S and Watkins DJ (2010) No -
8 Support Contactin 4 as an autism susceptibility locus. Cottrell CE , et al. (2011) Yes -
9 Support Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. Leblond CS , et al. (2012) Yes ID
10 Recent Recommendation Human-specific histone methylation signatures at transcription start sites in prefrontal neurons. Shulha HP , et al. (2012) No -
11 Support A discovery resource of rare copy number variations in individuals with autism spectrum disorder. Prasad A , et al. (2013) Yes -
12 Support Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders. Nava C , et al. (2013) Yes ID
13 Recent Recommendation Haplotype structure enables prioritization of common markers and candidate genes in autism spectrum disorder. Vardarajan BN , et al. (2013) No -
14 Positive Association A candidate gene association study further corroborates involvement of contactin genes in autism. Poot M (2014) Yes -
15 Negative Association No evidence for association of autism with rare heterozygous point mutations in Contactin-Associated Protein-Like 2 (CNTNAP2), or in Other Contacti... Murdoch JD , et al. (2015) Yes -
16 Positive Association Genome-wide Association Study of Autism Spectrum Disorder in the East Asian Populations. Liu X , et al. (2015) Yes -
17 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Lim ET , et al. (2017) Yes -
18 Support Genetic testing including targeted gene panel in a diverse clinical population of children with autism spectrum disorder: Findings and implications. Kalsner L , et al. (2017) Yes -
19 Positive Association Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Pardias AF , et al. (2018) No -
20 Highly Cited Overlapping and differential expression of BIG-2, BIG-1, TAG-1, and F3: four members of an axon-associated cell adhesion molecule subgroup of the i... Yoshihara Y , et al. (1995) No -
Rare Variants   (16)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo - - 15106122 Fernandez T , et al. (2004)
- - copy_number_loss Familial Paternal Multiplex 18349135 Roohi J , et al. (2008)
- - copy_number_gain Familial Paternal Simplex 18349135 Roohi J , et al. (2008)
- - copy_number_loss Familial - Multiplex 18374305 Christian SL , et al. (2008)
- - copy_number_loss - - Multiplex 19404257 Glessner JT , et al. (2009)
- - copy_number_gain - - Multiplex 19404257 Glessner JT , et al. (2009)
- - copy_number_loss Familial Maternal Multiplex 21308999 Cottrell CE , et al. (2011)
c.532A>G p.Asn178Asp missense_variant Familial Maternal - 21308999 Cottrell CE , et al. (2011)
c.662G>A p.Gly221Asp missense_variant Familial Maternal - 21308999 Cottrell CE , et al. (2011)
c.992A>G p.Glu331Gly missense_variant Familial Paternal - 21308999 Cottrell CE , et al. (2011)
c.1889A>G p.Tyr630Cys missense_variant Familial Paternal - 21308999 Cottrell CE , et al. (2011)
- - copy_number_loss Familial Maternal Simplex 22346768 Leblond CS , et al. (2012)
- - copy_number_gain Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_loss Unknown - Simplex 23632794 Nava C , et al. (2013)
T>C p.Ile605Thr missense_variant De novo - - 28714951 Lim ET , et al. (2017)
T>C - splice_site_variant Familial Paternal - 29271092 Kalsner L , et al. (2017)
Common Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.-145+105534C>T;c.-145+38822C>T Allele 1, G; allele 2, A intron_variant - - - 25337070 Poot M (2014)
c.56-9357T>C A/G intron_variant - - - 25337070 Poot M (2014)
c.-145+55783T>A;c.-145+57444T>A;c.-145+56773T>A;c.-145+56792T>A - intron_variant - - - 26314684 Liu X , et al. (2015)
c.-88-91778G>A - intron_variant - - - 29483656 Pardias AF , et al. (2018)
SFARI Gene score
2

Strong Candidate

2

Score Delta: Score remained at 2.1

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.

7/1/2017
2
icon
2

Score remained at 2

Description

Inherited (maternal and paternal) deletions observed in 7/~2000 unrelated cases and 0/~2500 controls, 1/7 unrelated individuals confirmed by qPCR (2 sibs actually confirmed). Statistical support for effect at this gene (4.7 x 10-4) is similar to that observed for either 15q11-13 or NRXN1, but still nominal given number of tests performed. Inherited duplications may also be enriched in cases with 7 unrelated probands carrying such events versus only 1 control (p = 0.0078) (Glessner JT et al.). Paternally inherited deletions observed in 2/3 autistic siblings from screen of 80 probands, paternally inherited duplication seen in a third unrelated child with autism, no similar event in > 750 controls including those from NIMH normal control initiative, resulting in nominal significance (Roohi J et al.). A translocation was also identified in an individual with autism (follow-up comment confirms diagnosis) (Fernandez T. et al.).

7/1/2015
2
icon
2

Score remained at 2

Description

Inherited (maternal and paternal) deletions observed in 7/~2000 unrelated cases and 0/~2500 controls, 1/7 unrelated individuals confirmed by qPCR (2 sibs actually confirmed). Statistical support for effect at this gene (4.7 x 10-4) is similar to that observed for either 15q11-13 or NRXN1, but still nominal given number of tests performed. Inherited duplications may also be enriched in cases with 7 unrelated probands carrying such events versus only 1 control (p = 0.0078) (Glessner JT et al.). Paternally inherited deletions observed in 2/3 autistic siblings from screen of 80 probands, paternally inherited duplication seen in a third unrelated child with autism, no similar event in > 750 controls including those from NIMH normal control initiative, resulting in nominal significance (Roohi J et al.). A translocation was also identified in an individual with autism (follow-up comment confirms diagnosis) (Fernandez T. et al.).

Reports Added
[Genome-wide Association Study of Autism Spectrum Disorder in the East Asian Populations.2015] [Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.2012] [BIG-2 mediates olfactory axon convergence to target glomeruli.2008] [Overlapping and differential expression of BIG-2, BIG-1, TAG-1, and F3: four members of an axon-associated cell adhesion molecule subgroup of the i...1995] [A candidate gene association study further corroborates involvement of contactin genes in autism.2014] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Human-specific histone methylation signatures at transcription start sites in prefrontal neurons.2012] [Contactin 4 as an autism susceptibility locus.2011] [Disruption of contactin 4 in three subjects with autism spectrum disorder.2008] [Disruption of contactin 4 (CNTN4) results in developmental delay and other features of 3p deletion syndrome.2004] [Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder.2008] [No evidence for association of autism with rare heterozygous point mutations in Contactin-Associated Protein-Like 2 (CNTNAP2), or in Other Contacti...2015] [Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders.2013] [Haplotype structure enables prioritization of common markers and candidate genes in autism spectrum disorder.2013] [Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.2009] [The protein tyrosine phosphatases PTPRZ and PTPRG bind to distinct members of the contactin family of neural recognition molecules.2010] [Disruption of Contactin 4 (CNTN4) results in developmental delay and other features of 3p deletion syndrome.2008]
1/1/2015
2
icon
2

Score remained at 2

Description

Inherited (maternal and paternal) deletions observed in 7/~2000 unrelated cases and 0/~2500 controls, 1/7 unrelated individuals confirmed by qPCR (2 sibs actually confirmed). Statistical support for effect at this gene (4.7 x 10-4) is similar to that observed for either 15q11-13 or NRXN1, but still nominal given number of tests performed. Inherited duplications may also be enriched in cases with 7 unrelated probands carrying such events versus only 1 control (p = 0.0078) (Glessner JT et al.). Paternally inherited deletions observed in 2/3 autistic siblings from screen of 80 probands, paternally inherited duplication seen in a third unrelated child with autism, no similar event in > 750 controls including those from NIMH normal control initiative, resulting in nominal significance (Roohi J et al.). A translocation was also identified in an individual with autism (follow-up comment confirms diagnosis) (Fernandez T. et al.).

7/1/2014
No data
icon
2

Increased from No data to 2

Description

Inherited (maternal and paternal) deletions observed in 7/~2000 unrelated cases and 0/~2500 controls, 1/7 unrelated individuals confirmed by qPCR (2 sibs actually confirmed). Statistical support for effect at this gene (4.7 x 10-4) is similar to that observed for either 15q11-13 or NRXN1, but still nominal given number of tests performed. Inherited duplications may also be enriched in cases with 7 unrelated probands carrying such events versus only 1 control (p = 0.0078) (Glessner JT et al.). Paternally inherited deletions observed in 2/3 autistic siblings from screen of 80 probands, paternally inherited duplication seen in a third unrelated child with autism, no similar event in > 750 controls including those from NIMH normal control initiative, resulting in nominal significance (Roohi J et al.). A translocation was also identified in an individual with autism (follow-up comment confirms diagnosis) (Fernandez T. et al.).

4/1/2014
No data
icon
2

Increased from No data to 2

Description

Inherited (maternal and paternal) deletions observed in 7/~2000 unrelated cases and 0/~2500 controls, 1/7 unrelated individuals confirmed by qPCR (2 sibs actually confirmed). Statistical support for effect at this gene (4.7 x 10-4) is similar to that observed for either 15q11-13 or NRXN1, but still nominal given number of tests performed. Inherited duplications may also be enriched in cases with 7 unrelated probands carrying such events versus only 1 control (p = 0.0078) (Glessner JT et al.). Paternally inherited deletions observed in 2/3 autistic siblings from screen of 80 probands, paternally inherited duplication seen in a third unrelated child with autism, no similar event in > 750 controls including those from NIMH normal control initiative, resulting in nominal significance (Roohi J et al.). A translocation was also identified in an individual with autism (follow-up comment confirms diagnosis) (Fernandez T. et al.).

Krishnan Probability Score

Score 0.50107912152258

Ranking 2038/25841 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 0.99660638792437

Ranking 1401/18225 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 0.94955751397458

Ranking 18139/18665 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 6

Ranking 254/461 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.
Zhang D Score

Score 0.4494921774675

Ranking 927/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
CNVs associated with CNTN4(1 CNVs)
3p26.3-p26.2 9 Duplication 16  /  17
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
AMY1A amylase, alpha 1A (salivary) Human Protein Binding 276 Q6NSB3
Ptprg protein tyrosine phosphatase, receptor type, G Mouse Protein Binding 19270 Q05909
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