Human Gene Module / Chromosome 16 / CNTNAP4

CNTNAP4Contactin associated protein-like 4

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
14 / 15
Rare Variants / Common Variants
22 / 1
Aliases
CNTNAP4, CASPR4
Associated Syndromes
-
Chromosome Band
16q23.1
Associated Disorders
SCZ, ADHD
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.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome Informatics
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CNTNAP4 (15 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 Contactin-Associated Proteins or Contactins 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 -
10 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
11 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
12 Support - Tuncay IO et al. (2022) Yes -
13 Support - Woodbury-Smith M et al. (2022) Yes -
14 Support - Zhou X et al. (2022) Yes -
15 Support - Sheth F et al. (2023) Yes DD, ID
Rare Variants   (22)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain De novo - - 21934709 Hanemaaijer NM , et al. (2011)
- - nonsynonymous_variant Unknown - Unknown 25549968 Li J , et al. (2015)
- - 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 Familial - Unknown 24870235 Karayannis T , et al. (2014)
c.320G>C p.Ser107Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2701G>A p.Ala901Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial Maternal Multiplex 20531469 Pinto D , et al. (2010)
c.3508G>A p.Asp1170Asn missense_variant De novo - - 28714951 Lim ET , et al. (2017)
c.3810T>C p.Tyr1270%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial Maternal Simplex 24870235 Karayannis T , et al. (2014)
- - copy_number_loss Familial Maternal Unknown 24870235 Karayannis T , et al. (2014)
c.1538A>G p.His513Arg missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.2701G>A p.Ala901Thr missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2008A>C p.Asn670His missense_variant De novo - - 35205252 Woodbury-Smith M et al. (2022)
c.2077A>G p.Ile693Val missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.3586G>A p.Val1196Met missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.1342_1371del p.Asn448_Leu457del inframe_deletion De novo - - 35982159 Zhou X et al. (2022)
c.3094A>T p.Asn1032Tyr missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
- - copy_number_gain Unknown - Possible multi-generational 20502679 Mefford HC , et al. (2010)
c.193+679_193+682del - intron_variant Familial Both parents Simplex 35190550 Tuncay IO et al. (2022)
c.3658_3661del p.Asp1220IlefsTer5 frameshift_variant Familial Maternal Simplex 37543562 Sheth F et al. (2023)
Common Variants   (1)
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)
SFARI Gene score
2

Strong Candidate

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.

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
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.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
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.

Reports Added
[New Scoring Scheme]
10/1/2017
3
icon
3

Decreased from 3 to 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.

Reports Added
[Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.2017]
7/1/2017
3
icon
3

Decreased from 3 to 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.

Reports Added
[Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.2017]
1/1/2016
3
icon
3

Decreased from 3 to 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.

Reports Added
[Functional impact of global rare copy number variation in autism spectrum disorders.2010] [Practical guidelines for interpreting copy number gains detected by high-resolution array in routine diagnostics.2011] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission.2014] [Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.2015] [No evidence for association of autism with rare heterozygous point mutations in Contactin-Associated Protein-Like 2 (CNTNAP2), or in Other Contacti...2015] [Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies.2010] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014]
1/1/2015
3
icon
3

Decreased from 3 to 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.

Reports Added
[Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.2015] [No evidence for association of autism with rare heterozygous point mutations in Contactin-Associated Protein-Like 2 (CNTNAP2), or in Other Contacti...2015]
7/1/2014
No data
icon
3

Increased from No data to 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.

4/1/2014
No data
icon
3

Increased from No data to 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.

Krishnan Probability Score

Score 0.49601152664103

Ranking 2716/25841 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.
Original Source
ExAC Score

Score 2.3431154940654E-5

Ranking 13811/18225 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
Original Source
Iossifov Probability Score

Score 0.933

Ranking 105/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.43046211177821

Ranking 321/18665 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).
Original Source
Larsen Cumulative Evidence Score

Score 4

Ranking 302/461 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.
Original Source
Zhang D Score

Score 0.10401043285861

Ranking 6043/20870 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.
Original Source
Interactome
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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