CNTN4contactin 4
Autism Reports / Total Reports
18 / 28Rare Variants / Common Variants
25 / 4Aliases
CNTN4, AXCAM, BIG-2, CNTN4A, MGC33615, CNTN4Associated Syndromes
-Chromosome Band
3p26.3-p26.2Associated Disorders
DD/NDD, IDRelevance 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.
External Links
SFARI Genomic Platforms
Reports related to CNTN4 (28 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 Contactin-Associated Proteins or Contactins | 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 developmental disorders | Schluth-Bolard C , et al. (2019) | No | Behavioral abnormalities |
| 21 | Support | Homozygous deletions implicate non-coding epigenetic marks in Autism spectrum disorder | Schmitz-Abe K et al. (2020) | Yes | - |
| 22 | Support | - | Oguro-Ando A et al. (2021) | No | - |
| 23 | Support | - | Zhao R et al. (2021) | Yes | - |
| 24 | Support | - | Woodbury-Smith M et al. (2022) | Yes | - |
| 25 | Support | - | Zhou X et al. (2022) | Yes | - |
| 26 | Support | - | Cirnigliaro M et al. (2023) | Yes | - |
| 27 | Support | - | Rosemary A Bamford et al. (2024) | No | - |
| 28 | 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 immunoglobulin superfamily | Yoshihara Y , et al. (1995) | No | - |
Rare Variants (25)
| 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) | |
| - | - | copy_number_loss | Familial | - | Multiplex | 18374305 | Christian SL , et al. (2008) | |
| - | - | copy_number_gain | Familial | Paternal | Simplex | 18349135 | Roohi J , et al. (2008) | |
| c.2128G>A | p.Gly710Arg | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.2542G>C | p.Glu848Gln | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| - | - | copy_number_loss | Familial | Paternal | Multiplex | 18349135 | Roohi J , et al. (2008) | |
| - | - | copy_number_loss | Familial | Both parents | - | 32820185 | Schmitz-Abe K et al. (2020) | |
| c.504T>C | p.Asn168%3D | synonymous_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| - | - | copy_number_loss | Familial | Maternal | Simplex | 22346768 | Leblond CS , et al. (2012) | |
| c.1278C>T | p.Val426%3D | synonymous_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.1398C>T | p.Asn466%3D | synonymous_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| - | - | 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.1942+2T>C | - | splice_site_variant | Familial | Paternal | - | 29271092 | Kalsner L , et al. (2017) | |
| c.1814T>C | p.Ile605Thr | missense_variant | De novo | - | Simplex | 28714951 | Lim ET , et al. (2017) | |
| c.324A>G | p.Thr108%3D | synonymous_variant | Unknown | - | - | 35205252 | Woodbury-Smith M et al. (2022) | |
| 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) | |
| c.1860del | p.Pro621LeufsTer44 | frameshift_variant | Familial | Maternal | Multiplex | 37506195 | Cirnigliaro M et al. (2023) |
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
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
criteria met
See SFARI Gene'scoring criteriaWe 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.
1/1/2021
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.).
7/1/2020
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.).
10/1/2019
Score remained at 2
New Scoring Scheme
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
[New Scoring Scheme]4/1/2019
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.).
7/1/2017
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
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
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
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
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
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
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ExAC Score
Score 0.99660638792437
Ranking 1401/18225 scored genes
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Sanders TADA Score
Score 0.94955751397458
Ranking 18139/18665 scored genes
[Show Scoring Methodology]
Larsen Cumulative Evidence Score
Score 6
Ranking 254/461 scored genes
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Zhang D Score
Score 0.4494921774675
Ranking 927/20870 scored genes
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External PIN Data
Interactome
- Protein Binding
- DNA Binding
- RNA Binding
- Protein Modification
- Direct Regulation
- ASD-Linked Genes
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 |