Human Gene Module / Chromosome 5 / PCDHA10

PCDHA10Protocadherin alpha 10

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
3 / 4
Rare Variants / Common Variants
2 / 5
Aliases
PCDHA10, CNR8,  CNRN8,  CNRS8,  CRNR8,  PCDH-ALPHA10
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Genetic Association
Chromosome Band
5q31.3
Associated Disorders
-
Relevance to Autism

Five SNPs within PCDHA10 (rs251379, rs1119032, rs17119271, rs155806, and rs17119346) showed significant association with autism in a family-based association study using 14 SNPs within the PCDHA gene cluster in 841 ASD families (574 of which were multiplex) obtained from the Autism Genetic Resource Exchange (AGRE) (Anitha et al., 2012).

Molecular Function

This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain.

Reports related to PCDHA10 (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Recent Recommendation Identification of CTCF as a master regulator of the clustered protocadherin genes. Golan-Mashiach M , et al. (2012) No -
2 Support De novo gene disruptions in children on the autistic spectrum. Iossifov I , et al. (2012) Yes -
3 Primary Protocadherin (PCDHA) as a novel susceptibility gene for autism. Anitha A , et al. (2012) Yes -
4 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes. Guo H , et al. (2018) Yes -
Rare Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2388+25867del - intron_variant De novo NA Simplex 22542183 Iossifov I , et al. (2012)
c.121G>C p.Gly41Arg missense_variant De novo NA Multiplex 30504930 Guo H , et al. (2018)
Common Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.2388+44410A>G - intron_variant - - - 23031252 Anitha A , et al. (2012)
c.2389-48828T>C - intron_variant - - - 23031252 Anitha A , et al. (2012)
c.2536+11686G>A - intron_variant - - - 23031252 Anitha A , et al. (2012)
c.2389-8694A>G T/C intron_variant - - - 23031252 Anitha A , et al. (2012)
c.2388+20901G>A T/C intron_variant - - - 23031252 Anitha A , et al. (2012)
SFARI Gene score
3

Suggestive Evidence

Five SNPs within PCDHA10 (rs251379, rs1119032, rs17119271, rs155806, and rs17119346) showed significant association with autism in a family-based association study using 14 SNPs within the PCDHA gene cluster in 841 ASD families (574 of which were multiplex) obtained from the Autism Genetic Resource Exchange (AGRE) (Anitha et al., 2012).

Score Delta: Score remained at 4

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

Five SNPs within PCDHA10 (rs251379, rs1119032, rs17119271, rs155806, and rs17119346) showed significant association with autism in a family-based association study using 14 SNPs within the PCDHA gene cluster in 841 ASD families (574 of which were multiplex) obtained from the Autism Genetic Resource Exchange (AGRE) (Anitha et al., 2012).

Reports Added
[New Scoring Scheme]
10/1/2018
4
icon
4

Decreased from 4 to 4

Description

Five SNPs within PCDHA10 (rs251379, rs1119032, rs17119271, rs155806, and rs17119346) showed significant association with autism in a family-based association study using 14 SNPs within the PCDHA gene cluster in 841 ASD families (574 of which were multiplex) obtained from the Autism Genetic Resource Exchange (AGRE) (Anitha et al., 2012).

4/1/2018
icon
4.3

Increased from to 4.3

Description

4

Krishnan Probability Score

Score 0.5180490438564

Ranking 1723/25841 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 4.1827181606915E-11

Ranking 17032/18225 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 0.94838500450907

Ranking 17662/18665 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 9

Ranking 200/461 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.
Zhang D Score

Score 0.14450857434938

Ranking 5292/20870 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.
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SFARI Gene Update

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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