Human Gene Module / Chromosome 9 / CNTNAP3

CNTNAP3contactin associated protein-like 3

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 7
Rare Variants / Common Variants
8 / 0
Aliases
CNTNAP3, RP11-204I2.1,  CASPR3,  CNTNAP3A,  RP11-138L21.1,  RP11-290L7.1
Associated Syndromes
-
Chromosome Band
9p12
Associated Disorders
-
Relevance to Autism

A rare mutation in the CNTNAP3 gene has been identified in a patient with Asperger syndrome (Vaags et al., 2012).

Molecular Function

The protein encoded by this gene belongs to the NCP family of cell-recognition molecules. This family represents a distinct subgroup of the neurexins. NCP proteins mediate neuron-glial interactions in vertebrates and glial-glial contact in invertebrates. The protein encoded by this gene may play a role in cell recognition within the nervous system. Alternatively spliced transcript variants encoding different isoforms have been described but their biological nature has not been determined.

SFARI Genomic Platforms
Reports related to CNTNAP3 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Rare deletions at the neurexin 3 locus in autism spectrum disorder Vaags AK , et al. (2012) Yes -
2 Support Caspr3-Deficient Mice Exhibit Low Motor Learning during the Early Phase of the Accelerated Rotarod Task Hirata H , et al. (2016) No -
3 Support Elevated mRNA expression of CASPR3 in patients with schizophrenia Okita M , et al. (2017) No -
4 Support Genomic Patterns of De Novo Mutation in Simplex Autism Turner TN et al. (2017) Yes -
5 Support The critical role of ASD-related gene CNTNAP3 in regulating synaptic development and social behavior in mice Tong DL , et al. (2019) Yes -
6 Support - Alonso-Gonzalez A et al. (2021) Yes -
7 Support - Zhou X et al. (2022) Yes -
Rare Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1944C>A p.Ser648Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3655C>T p.Arg1219Ter stop_gained De novo - Simplex 28965761 Turner TN et al. (2017)
c.1840C>G p.Pro614Ala missense_variant Familial Paternal Simplex 31150793 Tong DL , et al. (2019)
c.2356C>T p.Arg786Cys missense_variant Familial Paternal Simplex 31150793 Tong DL , et al. (2019)
c.2357G>A p.Arg786His missense_variant Familial Maternal Simplex 31150793 Tong DL , et al. (2019)
c.2330C>A p.Ala777Asp missense_variant De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.1228G>T p.Gly410Cys missense_variant Familial Paternal Simplex 22209245 Vaags AK , et al. (2012)
c.2765_2766insACTTGTGCTCATGAAGGAGTGGTTACTCCTGATGTTGGCTTGAGATATAAAAAGGGCTCTGTATTTGCACCAGAGCTATGAGATTT p.Thr923LeufsTer14 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Variants in the CNTNAP3 gene (a paternally-inherited missense variant and a rare de novo nonsense variant) have been identified in ASD probands (Vaags et al., 2012; Turner et al., 2017). Elevated levels of CNTNAP3 mRNA were observed in leukocytes in a cohort of 100 schizophrenia patients compared to 100 age-matched controls (Okita et al., 2017). CNTNAP3-deficient mice were found to exhibit deficits in motor learning during the early phase of the accelerated rotarod task in Hirata et al., 2016. Tong et al., 2019 reported additional ASD probands with inherited missense variants in the CNTNAP3 gene; functional analysis of two of these missense variants (p.Pro614Ala and p.Arg786Cys), as well as the de novo nonsense variant originally reported in Turner et al., 2017 (p.Arg1219Ter), demonstrated loss-of-function effects on excitatory and inhibitory synapse development. Furthermore, Tong et al., 2019 showed that male Cntnap3-null mice exhibited deficits in social interaction.

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.

1/1/2021
2
icon
2

Score remained at 2

Description

Variants in the CNTNAP3 gene (a paternally-inherited missense variant and a rare de novo nonsense variant) have been identified in ASD probands (Vaags et al., 2012; Turner et al., 2017). Elevated levels of CNTNAP3 mRNA were observed in leukocytes in a cohort of 100 schizophrenia patients compared to 100 age-matched controls (Okita et al., 2017). CNTNAP3-deficient mice were found to exhibit deficits in motor learning during the early phase of the accelerated rotarod task in Hirata et al., 2016. Tong et al., 2019 reported additional ASD probands with inherited missense variants in the CNTNAP3 gene; functional analysis of two of these missense variants (p.Pro614Ala and p.Arg786Cys), as well as the de novo nonsense variant originally reported in Turner et al., 2017 (p.Arg1219Ter), demonstrated loss-of-function effects on excitatory and inhibitory synapse development. Furthermore, Tong et al., 2019 showed that male Cntnap3-null mice exhibited deficits in social interaction.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Variants in the CNTNAP3 gene (a paternally-inherited missense variant and a rare de novo nonsense variant) have been identified in ASD probands (Vaags et al., 2012; Turner et al., 2017). Elevated levels of CNTNAP3 mRNA were observed in leukocytes in a cohort of 100 schizophrenia patients compared to 100 age-matched controls (Okita et al., 2017). CNTNAP3-deficient mice were found to exhibit deficits in motor learning during the early phase of the accelerated rotarod task in Hirata et al., 2016. Tong et al., 2019 reported additional ASD probands with inherited missense variants in the CNTNAP3 gene; functional analysis of two of these missense variants (p.Pro614Ala and p.Arg786Cys), as well as the de novo nonsense variant originally reported in Turner et al., 2017 (p.Arg1219Ter), demonstrated loss-of-function effects on excitatory and inhibitory synapse development. Furthermore, Tong et al., 2019 showed that male Cntnap3-null mice exhibited deficits in social interaction.

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
3

Decreased from 4 to 3

Description

Variants in the CNTNAP3 gene (a paternally-inherited missense variant and a rare de novo nonsense variant) have been identified in ASD probands (Vaags et al., 2012; Turner et al., 2017). Elevated levels of CNTNAP3 mRNA were observed in leukocytes in a cohort of 100 schizophrenia patients compared to 100 age-matched controls (Okita et al., 2017). CNTNAP3-deficient mice were found to exhibit deficits in motor learning during the early phase of the accelerated rotarod task in Hirata et al., 2016. Tong et al., 2019 reported additional ASD probands with inherited missense variants in the CNTNAP3 gene; functional analysis of two of these missense variants (p.Pro614Ala and p.Arg786Cys), as well as the de novo nonsense variant originally reported in Turner et al., 2017 (p.Arg1219Ter), demonstrated loss-of-function effects on excitatory and inhibitory synapse development. Furthermore, Tong et al., 2019 showed that male Cntnap3-null mice exhibited deficits in social interaction.

10/1/2018
icon
4

Increased from to 4

Description

Variants in the CNTNAP3 gene (a paternally-inherited missense variant and a rare de novo nonsense variant) have been identified in ASD probands (Vaags et al., 2012; Turner et al., 2017). Elevated levels of CNTNAP3 mRNA were observed in leukocytes in a cohort of 100 schizophrenia patients compared to 100 age-matched controls (Okita et al., 2017). CNTNAP3-deficient mice were found to exhibit deficits in motor learning during the early phase of the accelerated rotarod task in Hirata et al., 2016.

Krishnan Probability Score

Score 0.49194072031139

Ranking 4893/25841 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 0.072566365554852

Ranking 8167/18225 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 0.95044010135534

Ranking 18493/18665 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 0

Ranking 442/461 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.
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