Human Gene Module / Chromosome 5 / CTNND2

CTNND2Catenin (cadherin-associated protein), delta 2

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 6
Rare Variants / Common Variants
19 / 0
Aliases
CTNND2, GT24,  NPRAP
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
5p15.2
Associated Disorders
-
Relevance to Autism

Missense variants at conserved residues of the CTNND2 gene were found to be significantly more frequent in autism cases than in controls (P=0.04 vs. 1000 Genomes Project; P=7.8E-04 vs. Exome Variant Server); several of these missense variants exhibited loss-of-function effects by functional analysis in zebrafish embryos and cultured hippocampal neurons (Turner et al., 2015).

Molecular Function

This gene encodes an adhesive junction associated protein of the armadillo/beta-catenin superfamily and is implicated in brain and eye development and cancer formation.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBase
Mouse
Entrez GeneMouse Genome Informatics
Fruit fly
Entrez Gene
Zebrafish
Entrez Gene
Reports related to CTNND2 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Loss of -catenin function in severe autism. Turner TN , et al. (2015) Yes -
2 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
3 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies. Redin C , et al. (2016) No -
4 Support Whole-Genome Sequencing of Cytogenetically Balanced Chromosome Translocations Identifies Potentially Pathological Gene Disruptions and Highlights t... Nilsson D , et al. (2016) No -
5 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model. Guo H , et al. (2018) Yes -
6 Support A child with autism, behavioral issues, and dysmorphic features found to have a tandem duplication within CTNND2 by mate-pair sequencing. Miller DE , et al. (2019) Yes -
Rare Variants   (19)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo NA - 27841880 Redin C , et al. (2016)
- - copy_number_gain De novo NA Simplex 31814264 Miller DE , et al. (2019)
- - translocation Familial Maternal Simplex 27862604 Nilsson D , et al. (2016)
- - copy_number_loss Familial Maternal Unknown 25807484 Turner TN , et al. (2015)
- - copy_number_loss Familial Paternal Unknown 25807484 Turner TN , et al. (2015)
c.100G>A p.Gly34Ser missense_variant Unknown - Unknown 25807484 Turner TN , et al. (2015)
c.2087C>T p.Ser696Leu missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.2467G>A p.Asp823Asn missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.566C>T p.Pro189Leu missense_variant Unknown - Unknown 25807484 Turner TN , et al. (2015)
c.671C>T p.Pro224Leu missense_variant Unknown - Unknown 25807484 Turner TN , et al. (2015)
c.823G>T p.Gly275Cys missense_variant Unknown - Unknown 25807484 Turner TN , et al. (2015)
c.1520A>C p.Gln507Pro missense_variant Unknown - Simplex 25807484 Turner TN , et al. (2015)
c.1361G>A p.Arg454His missense_variant Unknown - Unknown 25807484 Turner TN , et al. (2015)
c.2137C>T p.Arg713Cys missense_variant Unknown - Unknown 25807484 Turner TN , et al. (2015)
c.2585C>T p.Thr862Met missense_variant Unknown - Unknown 25807484 Turner TN , et al. (2015)
c.214G>A p.Glu72Lys missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.2087C>T p.Ser696Leu missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.100G>A p.Gly34Ser missense_variant Familial Maternal Multiplex 25807484 Turner TN , et al. (2015)
c.2137C>T p.Arg713Cys missense_variant Familial Maternal Multiplex 25807484 Turner TN , et al. (2015)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Exome sequencing of 13 unrelated female ASD patients from multiplex families with severe autism identified two missense variants in the CTNND2 gene. Additional sequencing of ASD cases and controls determined that missense variants at conserved residues of the CTNND2 gene were found to be significantly more frequent in autism cases than in controls (P=0.04 vs. 1000 Genomes Project; P=7.8E-04 vs. Exome Variant Server). Although segregation of these variants was incomplete or not determined in many cases, functional analysis of ASD-associated CTNND2 missense variants in zebrafish embryos and cultured hippocampal neurons identified several missense variants that exhibited loss-of-function effects (PMID 25807484). In the same report, a comparison of dosage imbalances (deletions, duplications, and unbalanced translocations) affecting the CTNND2 gene in 19,556 cases and 13,898 controls from PMID 22521361 found 25 instances in cases and three in controls, corresponding to an odds ratio of 5.9 (P=4.10 x 10-4).

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.

1/1/2020
2
icon
2

Score remained at 2

Description

Exome sequencing of 13 unrelated female ASD patients from multiplex families with severe autism identified two missense variants in the CTNND2 gene. Additional sequencing of ASD cases and controls determined that missense variants at conserved residues of the CTNND2 gene were found to be significantly more frequent in autism cases than in controls (P=0.04 vs. 1000 Genomes Project; P=7.8E-04 vs. Exome Variant Server). Although segregation of these variants was incomplete or not determined in many cases, functional analysis of ASD-associated CTNND2 missense variants in zebrafish embryos and cultured hippocampal neurons identified several missense variants that exhibited loss-of-function effects (PMID 25807484). In the same report, a comparison of dosage imbalances (deletions, duplications, and unbalanced translocations) affecting the CTNND2 gene in 19,556 cases and 13,898 controls from PMID 22521361 found 25 instances in cases and three in controls, corresponding to an odds ratio of 5.9 (P=4.10 x 10-4).

Reports Added
[A child with autism, behavioral issues, and dysmorphic features found to have a tandem duplication within CTNND2 by mate-pair sequencing.2019]
10/1/2019
2
icon
2

Score remained at 2

New Scoring Scheme
Description

Exome sequencing of 13 unrelated female ASD patients from multiplex families with severe autism identified two missense variants in the CTNND2 gene. Additional sequencing of ASD cases and controls determined that missense variants at conserved residues of the CTNND2 gene were found to be significantly more frequent in autism cases than in controls (P=0.04 vs. 1000 Genomes Project; P=7.8E-04 vs. Exome Variant Server). Although segregation of these variants was incomplete or not determined in many cases, functional analysis of ASD-associated CTNND2 missense variants in zebrafish embryos and cultured hippocampal neurons identified several missense variants that exhibited loss-of-function effects (PMID 25807484). In the same report, a comparison of dosage imbalances (deletions, duplications, and unbalanced translocations) affecting the CTNND2 gene in 19,556 cases and 13,898 controls from PMID 22521361 found 25 instances in cases and three in controls, corresponding to an odds ratio of 5.9 (P=4.10 x 10-4).

Reports Added
[New Scoring Scheme]
1/1/2019
2
icon
2

Score remained at 2

Description

Exome sequencing of 13 unrelated female ASD patients from multiplex families with severe autism identified two missense variants in the CTNND2 gene. Additional sequencing of ASD cases and controls determined that missense variants at conserved residues of the CTNND2 gene were found to be significantly more frequent in autism cases than in controls (P=0.04 vs. 1000 Genomes Project; P=7.8E-04 vs. Exome Variant Server). Although segregation of these variants was incomplete or not determined in many cases, functional analysis of ASD-associated CTNND2 missense variants in zebrafish embryos and cultured hippocampal neurons identified several missense variants that exhibited loss-of-function effects (PMID 25807484). In the same report, a comparison of dosage imbalances (deletions, duplications, and unbalanced translocations) affecting the CTNND2 gene in 19,556 cases and 13,898 controls from PMID 22521361 found 25 instances in cases and three in controls, corresponding to an odds ratio of 5.9 (P=4.10 x 10-4).

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
1/1/2017
2
icon
2

Score remained at 2

Description

Exome sequencing of 13 unrelated female ASD patients from multiplex families with severe autism identified two missense variants in the CTNND2 gene. Additional sequencing of ASD cases and controls determined that missense variants at conserved residues of the CTNND2 gene were found to be significantly more frequent in autism cases than in controls (P=0.04 vs. 1000 Genomes Project; P=7.8E-04 vs. Exome Variant Server). Although segregation of these variants was incomplete or not determined in many cases, functional analysis of ASD-associated CTNND2 missense variants in zebrafish embryos and cultured hippocampal neurons identified several missense variants that exhibited loss-of-function effects (PMID 25807484). In the same report, a comparison of dosage imbalances (deletions, duplications, and unbalanced translocations) affecting the CTNND2 gene in 19,556 cases and 13,898 controls from PMID 22521361 found 25 instances in cases and three in controls, corresponding to an odds ratio of 5.9 (P=4.10 x 10-4).

Reports Added
[Whole-Genome Sequencing of Cytogenetically Balanced Chromosome Translocations Identifies Potentially Pathological Gene Disruptions and Highlights t...2016]
10/1/2016
2
icon
2

Score remained at 2

Description

Exome sequencing of 13 unrelated female ASD patients from multiplex families with severe autism identified two missense variants in the CTNND2 gene. Additional sequencing of ASD cases and controls determined that missense variants at conserved residues of the CTNND2 gene were found to be significantly more frequent in autism cases than in controls (P=0.04 vs. 1000 Genomes Project; P=7.8E-04 vs. Exome Variant Server). Although segregation of these variants was incomplete or not determined in many cases, functional analysis of ASD-associated CTNND2 missense variants in zebrafish embryos and cultured hippocampal neurons identified several missense variants that exhibited loss-of-function effects (PMID 25807484). In the same report, a comparison of dosage imbalances (deletions, duplications, and unbalanced translocations) affecting the CTNND2 gene in 19,556 cases and 13,898 controls from PMID 22521361 found 25 instances in cases and three in controls, corresponding to an odds ratio of 5.9 (P=4.10 x 10-4).

Reports Added
[De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016]
4/1/2015
icon
2

Increased from to 2

Description

Exome sequencing of 13 unrelated female ASD patients from multiplex families with severe autism identified two missense variants in the CTNND2 gene. Additional sequencing of ASD cases and controls determined that missense variants at conserved residues of the CTNND2 gene were found to be significantly more frequent in autism cases than in controls (P=0.04 vs. 1000 Genomes Project; P=7.8E-04 vs. Exome Variant Server). Although segregation of these variants was incomplete or not determined in many cases, functional analysis of ASD-associated CTNND2 missense variants in zebrafish embryos and cultured hippocampal neurons identified several missense variants that exhibited loss-of-function effects (PMID 25807484). In the same report, a comparison of dosage imbalances (deletions, duplications, and unbalanced translocations) affecting the CTNND2 gene in 19,556 cases and 13,898 controls from PMID 22521361 found 25 instances in cases and three in controls, corresponding to an odds ratio of 5.9 (P=4.10 x 10-4).

Krishnan Probability Score

Score 0.76543448442852

Ranking 16/25841 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 0.99999995194447

Ranking 171/18225 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
Sanders TADA Score

Score 0.64954485207366

Ranking 894/18665 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
Zhang D Score

Score 0.33298497289561

Ranking 2248/20870 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
ARHGEF28 Rho guanine nucleotide exchange factor (GEF) 28 Human Protein Binding 64283 Q8N1W1
CCDC85A coiled-coil domain containing 85A Human Protein Binding 114800 Q96PX6
CCDC85B coiled-coil domain containing 85B Human Protein Binding 11007 Q15834
Cttn cortactin Mouse Protein Binding 13043 Q60598
Dact1 dapper homolog 1, antagonist of beta-catenin (xenopus) Mouse Protein Binding 59036 Q8R4A3
Dact2 dapper homolog 2, antagonist of beta-catenin (xenopus) Mouse Protein Binding 240025 Q7TN08
DNM1 dynamin 1 Human Protein Binding 1759 Q05193
GCH1 GTP cyclohydrolase 1 Human Protein Binding 2643 P30793
GLTP glycolipid transfer protein Human Protein Binding 51228 Q9NZD2
Grip2 glutamate receptor interacting protein 2 Rat Protein Binding 171571 Q9WTW1
HES1 hairy and enhancer of split 1, (Drosophila) Human DNA Binding 3280 Q14469
LNX1 ligand of numb-protein X 1, E3 ubiquitin protein ligase Human Protein Modification 84708 Q8TBB1
LRRC7 leucine rich repeat containing 7 Human Protein Binding 57554 Q96NW7
Pdzd2 PDZ domain containing 2 Rat Protein Binding 65034 Q9QZR8
PRR36 proline rich 36 Human Protein Binding 80164 Q9H6K5
Sphk1 sphingosine kinase 1 Mouse Protein Binding 20698 Q8CI15
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We are pleased to announce some changes to the ongoing curation of the data in SFARI Gene. In the context of a continued effort to develop the human gene module and its manually curated list of autism risk genes, we are modifying other aspects of the site to focus on the information that is of greatest interest to the research community. The version of SFARI Gene that has been developed until now will be frozen and will remain available as “SFARI Gene Archive”. Please see the announcement for more details.
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