Human Gene Module / Chromosome 16 / CNTNAP4

CNTNAP4Contactin associated protein-like 4

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
8 / 9
Rare Variants / Common Variants
15 / 2
Aliases
CNTNAP4, CASPR4
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Functional
Chromosome Band
16q23.1
Associated Disorders
ADHD, SCZ
Relevance to Autism

Cntnap4 mutant mice display augmented midbrain dopaminergic release in the nucleus accumbens, a severe and highly penetrant over-grooming behavior, elevated startle responses and abnormal PPI indexes. Furthermore, deletions involving the CNTNAP4 gene were identified in patients with ASD, ADHD, and schizophrenia (Karayannis et al., 2014).

Molecular Function

This gene product belongs to the neurexin family, members of which function in the vertebrate nervous system as cell adhesion molecules and receptors.

Reports related to CNTNAP4 (9 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies. Mefford HC , et al. (2010) No -
2 Support Functional impact of global rare copy number variation in autism spectrum disorders. Pinto D , et al. (2010) Yes -
3 Support Practical guidelines for interpreting copy number gains detected by high-resolution array in routine diagnostics. Hanemaaijer NM , et al. (2011) Yes -
4 Support Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. O'Roak BJ , et al. (2012) Yes -
5 Primary Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission. Karayannis T , et al. (2014) Yes SCZ, ADHD
6 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
7 Recent Recommendation Integrated systems analysis reveals a molecular network underlying autism spectrum disorders. Li J , et al. (2015) Yes -
8 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 -
9 Recent recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
Rare Variants   (15)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain Unknown - Possible multi-generational 20502679 Mefford HC , et al. (2010)
- - copy_number_loss Familial Maternal Multiplex 20531469 Pinto D , et al. (2010)
- - copy_number_gain De novo - - 21934709 Hanemaaijer NM , et al. (2011)
- - copy_number_loss De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
- - copy_number_loss Unknown - Unknown 24870235 Karayannis T , et al. (2014)
- - copy_number_loss Inherited - Unknown 24870235 Karayannis T , et al. (2014)
- - copy_number_loss Unknown - Unknown 24870235 Karayannis T , et al. (2014)
- - copy_number_loss Unknown - Unknown 24870235 Karayannis T , et al. (2014)
- - copy_number_loss Unknown - Unknown 24870235 Karayannis T , et al. (2014)
- - copy_number_loss Familial Maternal Unknown 24870235 Karayannis T , et al. (2014)
- - copy_number_loss Familial Maternal Unknown 24870235 Karayannis T , et al. (2014)
- - copy_number_loss Familial Maternal Multi-generational 24870235 Karayannis T , et al. (2014)
c.3246A>T p.Asn1082Tyr missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.2077A>G p.Gln693Arg missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
- - nonsynonymous_variant Unknown - Unknown 25549968 Li J , et al. (2015)
Common Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- - downstream_gene_variant - - - 24870235 Karayannis T , et al. (2014)
- - downstream_gene_variant - - - 24870235 Karayannis T , et al. (2014)
SFARI Gene score
3

Suggestive Evidence

A de novo, likely gene-disruptive deletion involving the CNTNAP4 gene was identified in a simplex ASD case from the Simons Simplex Collection (PMID 22495309). More recently, a survey of an independent cohort of 784 ASD cases identified two unrelated patients carrying maternally-inherited deletions affecting at least one exon of CNTNAP4 (PMID 24870235). Furthermore, a screen for CNVs within the CNTNAP4 locus in 2,078 ASD cases, 1,241 ADHD cases, 965 schizophrenia cases, and 8,087 combined controls in this report determined that two cases from each cohort were found to carry a CNTNAP4 intronic deletion; none of the controls were found to harbor CNVs affecting this gene (combined P-value of <0.002). Two CNTNAP4 SNPs were also identified that showed gene-wide association with schizophrenia in a sample of 232 schizophrenia cases and their families.

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

04-01-2017
3

Initial score established: 3

Description

A de novo, likely gene-disruptive deletion involving the CNTNAP4 gene was identified in a simplex ASD case from the Simons Simplex Collection (PMID 22495309). More recently, a survey of an independent cohort of 784 ASD cases identified two unrelated patients carrying maternally-inherited deletions affecting at least one exon of CNTNAP4 (PMID 24870235). Furthermore, a screen for CNVs within the CNTNAP4 locus in 2,078 ASD cases, 1,241 ADHD cases, 965 schizophrenia cases, and 8,087 combined controls in this report determined that two cases from each cohort were found to carry a CNTNAP4 intronic deletion; none of the controls were found to harbor CNVs affecting this gene (combined P-value of <0.002). Two CNTNAP4 SNPs were also identified that showed gene-wide association with schizophrenia in a sample of 232 schizophrenia cases and their families.

CNVs associated with CNTNAP4(1 CNVs)
16q23.1 30 Deletion-Duplication 51  /  249
Animal Models associated with CNTNAP4(7 Models)
Cntnap4_1_KO_HT Genetic
Cntnap4_1_KO_HT-Halo RESCUE-Pharmaceutical
Cntnap4_1_KO_HT-Indi RESCUE-Pharmaceutical
Cntnap4_2_KO_HM Genetic
Cntnap4_2_KO_HM-Indi RESCUE-Pharmaceutical
Cntnap4_3_KO_HM Genetic
Cntnap4_4_KO_HM-PV-Cre-RFP Genetic
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
MAST3 microtubule associated serine/threonine kinase 3 Human Protein Binding 23031 O60307
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