Human Gene Module / Chromosome 3 / CNTN4

CNTN4contactin 4

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
13 / 21
Rare Variants / Common Variants
17 / 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 (21 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 Support Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with develop... Schluth-Bolard C , et al. (2019) No Behavioral abnormalities
21 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   (17)
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 Unknown - Simplex 23632794 Nava C , et al. (2013)
- - copy_number_gain - - Multiplex 19404257 Glessner JT , et al. (2009)
- - copy_number_loss - - Multiplex 19404257 Glessner JT , et al. (2009)
- - copy_number_gain Unknown - Unknown 23275889 Prasad A , et al. (2013)
T>C p.Ile605Thr missense_variant De novo - - 28714951 Lim ET , et al. (2017)
- - copy_number_loss Familial - Multiplex 18374305 Christian SL , et al. (2008)
- - copy_number_gain Familial Paternal Simplex 18349135 Roohi J , et al. (2008)
T>C - splice_site_variant Familial Paternal - 29271092 Kalsner L , et al. (2017)
- - copy_number_loss Familial Paternal Multiplex 18349135 Roohi J , et al. (2008)
- - copy_number_loss Familial Maternal Simplex 22346768 Leblond CS , et al. (2012)
- - copy_number_loss Familial Maternal Multiplex 21308999 Cottrell CE , et al. (2011)
- - complex_structural_alteration De novo - - 30923172 Schluth-Bolard C , et al. (2019)
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)
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.-145+55783T>A;c.-145+57444T>A;c.-145+56773T>A;c.-145+56792T>A - intron_variant - - - 26314684 Liu X , et al. (2015)
c.56-9357T>C A/G intron_variant - - - 25337070 Poot M (2014)
c.-88-91778G>A - intron_variant - - - 29483656 Pardias AF , et al. (2018)
SFARI Gene score
2

Strong Candidate

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.).

Score Delta: Score remained at 2

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

10/1/2014
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.
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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