Human Gene Module / Chromosome 18 / CDH2

CDH2cadherin 2

SFARI Gene Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
5 / 8
Rare Variants / Common Variants
14 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
18q12.1
Associated Disorders
-
Relevance to Autism

Several de novo coding variants in the CDH2 gene, including a de novo missense variant that was predicted to be damaging, have been identified in ASD probands (Iossifov et al., 2014; Takata et al., 2018; Zhou et al., 2022; Miyake et al., 2023). Accogli et al., 2019 reported nine individuals with de novo heterozygous variants in the CDH2 gene presenting with a syndromic neurodevelopmental disorder characterized by global developmental delay and/or intellectual disability, variable axon pathfinding defects, ocular, cardiac, and genital anomalies; five of the de novo CDH2 missense variants identified in this report, including two that were identified in individuals who were reported to have autism, were experimentally shown to result in impaired cell-cell adhesion. A homozygous missense variant in the CDH2 gene (p.His150Tyr) was identified in three siblings born to consanguineous Bedouin parents who met DSM-5 criteria for ADHD; one of these individuals also presented with mild developmental delay and autism spectrum disorder (Halperin et al., 2021). Additional functional studies in Halperin et al., 2021 using a CRISPR/Cas9-mutated knock-in mice harboring the CHD2 p.His150Tyr variant in the mouse ortholog recapitulated core behavioral features of hyperactivity; mutant mice also exhibited impaired pre-synaptic vesicle clustering, attenuated evoked transmitted release, and decreased spontaneous release. Rare missense variants in the CDH2 gene have been identified in probands with obsessive-compulsive behavior (OCD) and Tourette syndrome (Moya et al., 2013).

Molecular Function

This gene encodes a classical cadherin and member of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein is proteolytically processed to generate a calcium-dependent cell adhesion molecule and glycoprotein. This protein plays a role in the establishment of left-right asymmetry, development of the nervous system and the formation of cartilage and bone.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
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Reports related to CDH2 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Moya PR et al. (2013) No -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
4 Support - Accogli A et al. (2019) No ASD, ADHD, ID, epilepsy/seizures
5 Support - Halperin D et al. (2021) No ASD, DD
6 Support - Zhou X et al. (2022) Yes -
7 Primary - Miyake N et al. (2023) Yes -
8 Support - Sheth F et al. (2023) Yes DD, ID
Rare Variants   (14)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.792A>G p.Arg264= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.1057G>A p.Asp353Asn missense_variant De novo - - 31585109 Accogli A et al. (2019)
c.1789G>A p.Asp597Asn missense_variant De novo - - 31585109 Accogli A et al. (2019)
c.1789G>T p.Asp597Tyr missense_variant De novo - - 31585109 Accogli A et al. (2019)
c.1802A>C p.Asn601Thr missense_variant De novo - - 31585109 Accogli A et al. (2019)
c.1839C>G p.Cys613Trp missense_variant De novo - - 31585109 Accogli A et al. (2019)
c.1880A>G p.Asp627Gly missense_variant De novo - - 31585109 Accogli A et al. (2019)
c.2027A>G p.Tyr676Cys missense_variant De novo - - 31585109 Accogli A et al. (2019)
c.670C>T p.Pro224Ser missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.2526G>A p.Ala842= synonymous_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.772A>G p.Ile258Val missense_variant Familial Paternal Simplex 37543562 Sheth F et al. (2023)
c.2470_2471del p.Leu824ValfsTer4 frameshift_variant De novo - - 31585109 Accogli A et al. (2019)
c.2471_2472insTGTT p.Leu825ValfsTer5 frameshift_variant De novo - - 31585109 Accogli A et al. (2019)
c.355C>T p.His150Tyr missense_variant Familial Both parents Multiplex 34702855 Halperin D et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
3S

Suggestive Evidence, Syndromic

Score Delta: Score remained at 3S

criteria met
See SFARI Gene'scoring criteria
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.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

7/1/2023
icon
3S

Increased from to 3S

Krishnan Probability Score

Score 0.61449566446394

Ranking 130/25841 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 0.89744093123646

Ranking 3245/18225 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 0.94470704627899

Ranking 16181/18665 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 -0.19719033129124

Ranking 15368/20870 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
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