Human Gene Module / Chromosome 3 / CNTN4

CNTN4contactin 4

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
11 / 17
Rare Variants / Common Variants
14 / 3
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 (17 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 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   (14)
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)
Common Variants   (3)
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)
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.).

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.

04-01-2017
2

Initial score established: 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.).

CNVs associated with CNTN4(1 CNVs)
3p26.3-p26.2 8 Duplication 14  /  14
Animal Models associated with CNTN4(1 Models)
CNTN4_1_KI_HM Genetic
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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