Human Gene Module / Chromosome 16 / CDH8

CDH8cadherin 8, type 2

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
5 / 10
Rare Variants / Common Variants
9 / 0
Aliases
CDH8, Cadherin-8
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
16q21
Associated Disorders
-
Relevance to Autism

Rare mutations in the CDH8 gene have been identified with autism (Pagnamenta et al., 2011).

Molecular Function

An integral membrane proteins that mediates calcium-dependent cell-cell adhesion

Reports related to CDH8 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Expression of Dbx1, Neurogenin 2, Semaphorin 5A, Cadherin 8, and Emx1 distinguish ventral and lateral pallial histogenetic divisions in the develop... Medina L , et al. (2004) No -
2 Recent Recommendation Absence of layer-specific cadherin expression profiles in the neocortex of the reeler mutant mouse. Hertel N and Redies C (2010) No -
3 Primary Rare familial 16q21 microdeletions under a linkage peak implicate cadherin 8 (CDH8) in susceptibility to autism and learning disability. Pagnamenta AT , et al. (2010) Yes -
4 Recent Recommendation Cadherin expression in the somatosensory cortex: evidence for a combinatorial molecular code at the single-cell level. Krishna-K K , et al. (2010) No -
5 Support Identification of candidate intergenic risk loci in autism spectrum disorder. Walker S and Scherer SW (2013) Yes -
6 Recent Recommendation Cadherin-8 expression, synaptic localization, and molecular control of neuronal form in prefrontal corticostriatal circuits. Friedman LG , et al. (2014) No -
7 Support Frequency and Complexity of De Novo Structural Mutation in Autism. Brandler WM , et al. (2016) Yes -
8 Support Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior. Doan RN , et al. (2016) Yes -
9 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. Monies D , et al. (2019) Yes Speech delay, developmental regression
10 Highly Cited Cloning of five human cadherins clarifies characteristic features of cadherin extracellular domain and provides further evidence for two structural... Tanihara H , et al. (1994) No -
Rare Variants   (9)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - inversion De novo NA - 27018473 Brandler WM , et al. (2016)
A>G - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
G>A - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
TA>CT - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
- - copy_number_loss Familial Maternal Simplex 23879678 Walker S and Scherer SW (2013)
- - copy_number_loss Familial Paternal Simplex 23879678 Walker S and Scherer SW (2013)
- - copy_number_loss Familial Maternal Multiplex 20972252 Pagnamenta AT , et al. (2010)
c.476A>C p.Asp159Ala missense_variant Unknown - Unknown 31130284 Monies D , et al. (2019)
- - copy_number_loss Familial Paternal Multi-generational 20972252 Pagnamenta AT , et al. (2010)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Single gene inherited CNVs were found in two independent families with autism and/or learning disability; similar events were absent in >5000 controls (Pagnamenta et al., 2011). Inherited deletions adjacent to CHD8 were observed in two unrelated ASD probands but not in >3600 controls (Walker and Scherer, 2013). Whole genome sequencing of 235 subjects, including 71 ASD probands, identified a de novo inversion disrupting CHD8 in a male ASD proband (Brandler et al., 2016).

Score Delta: Decreased from 4 to 3

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.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Single gene inherited CNVs were found in two independent families with autism and/or learning disability; similar events were absent in >5000 controls (Pagnamenta et al., 2011). Inherited deletions adjacent to CHD8 were observed in two unrelated ASD probands but not in >3600 controls (Walker and Scherer, 2013). Whole genome sequencing of 235 subjects, including 71 ASD probands, identified a de novo inversion disrupting CHD8 in a male ASD proband (Brandler et al., 2016).

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

Decreased from 4 to 4

Description

Single gene inherited CNVs were found in two independent families with autism and/or learning disability; similar events were absent in >5000 controls (Pagnamenta et al., 2011). Inherited deletions adjacent to CHD8 were observed in two unrelated ASD probands but not in >3600 controls (Walker and Scherer, 2013). Whole genome sequencing of 235 subjects, including 71 ASD probands, identified a de novo inversion disrupting CHD8 in a male ASD proband (Brandler et al., 2016).

10/1/2016
4
icon
4

Decreased from 4 to 4

Description

Single gene inherited CNVs were found in two independent families with autism and/or learning disability; similar events were absent in >5000 controls (Pagnamenta et al., 2011). Inherited deletions adjacent to CHD8 were observed in two unrelated ASD probands but not in >3600 controls (Walker and Scherer, 2013). Whole genome sequencing of 235 subjects, including 71 ASD probands, identified a de novo inversion disrupting CHD8 in a male ASD proband (Brandler et al., 2016).

4/1/2016
4
icon
4

Decreased from 4 to 4

Description

Single gene inherited CNVs were found in two independent families with autism and/or learning disability; similar events were absent in >5000 controls (Pagnamenta et al., 2011). Inherited deletions adjacent to CHD8 were observed in two unrelated ASD probands but not in >3600 controls (Walker and Scherer, 2013). Whole genome sequencing of 235 subjects, including 71 ASD probands, identified a de novo inversion disrupting CHD8 in a male ASD proband (Brandler et al., 2016).

4/1/2014
No data
icon
4

Increased from No data to 4

Description

Single gene inherited CNVS were found in two independent families with autism. Similar events were absent in >5000 controls (PMID 20972252).

Krishnan Probability Score

Score 0.61446245131877

Ranking 132/25841 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 0.99746377127181

Ranking 1320/18225 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 0.94278846154914

Ranking 15439/18665 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).
Zhang D Score

Score 0.31074673814736

Ranking 2582/20870 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.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
ARVCF armadillo repeat gene deleted in velocardiofacial syndrome Human Protein Binding 421 O00192
BCAM EHMT1 Human Protein Binding 4059 P50895
CTNND1 catenin (cadherin-associated protein), delta 1 Human Protein Binding 1500 O60716
EXOG endo/exonuclease (5'-3'), endonuclease G-like Human Protein Binding 9941 Q9Y2C4
LOC100510688 Human Protein Binding Q5SP12
NYNRIN NYN domain and retroviral integrase containing Human Protein Binding 57523 Q9P2P1
PLD2 phospholipase D2 Human Protein Binding 5338 I3L2C9
TMTC4 transmembrane and tetratricopeptide repeat containing 4 Human Protein Binding 84899 Q5T4D3
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