Human Gene Module / Chromosome 5 / PCDHA2

PCDHA2Protocadherin alpha 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 6
Rare Variants / Common Variants
5 / 5
Aliases
PCDHA2, PCDH-ALPHA2
Associated Syndromes
-
Chromosome Band
5q31.3
Associated Disorders
-
Relevance to Autism

Five SNPs within PCDHA2 (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). A de novo missense variant that was predicted to be damaging in the PCDHA2 gene was observed in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; this variant was later reported to be a postzygotic mosaic mutation (Allele Fraction 0.38) in Lim et al., 2017.

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.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PCDHA2 (6 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 The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
5 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
6 Support - Suhua Chang et al. () Yes -
Rare Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2388+86951del - intron_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.659C>A p.Pro220His missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1428G>C p.Thr476= synonymous_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2295del p.Lys766ArgfsTer29 frameshift_variant De novo - Simplex 39126614 Suhua Chang et al. ()
c.1528del p.Val510CysfsTer26 frameshift_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
Common Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.2389-48828T>C - intron_variant - - - 23031252 Anitha A , et al. (2012)
c.2389-76103A>G - 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+81985G>A T/C intron_variant - - - 23031252 Anitha A , et al. (2012)
SFARI Gene score
2

Strong Candidate

Five SNPs within PCDHA2 (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). A de novo missense variant that was predicted to be damaging in the PCDHA2 gene was observed in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; this variant was later reported to be a postzygotic mosaic mutation (Allele Fraction 0.38) in Lim et al., 2017.

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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Five SNPs within PCDHA2 (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). A de novo missense variant that was predicted to be damaging in the PCDHA2 gene was observed in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; this variant was later reported to be a postzygotic mosaic mutation (Allele Fraction 0.38) in Lim et al., 2017.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Five SNPs within PCDHA2 (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). A de novo missense variant that was predicted to be damaging in the PCDHA2 gene was observed in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; this variant was later reported to be a postzygotic mosaic mutation (Allele Fraction 0.38) in Lim et al., 2017.

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

Decreased from 4 to 4

Description

Five SNPs within PCDHA2 (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). A de novo missense variant that was predicted to be damaging in the PCDHA2 gene was observed in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; this variant was later reported to be a postzygotic mosaic mutation (Allele Fraction 0.38) in Lim et al., 2017.

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
7/1/2018
icon
4

Increased from to 4

Description

Five SNPs within PCDHA2 (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). A de novo missense variant that was predicted to be damaging in the PCDHA2 gene was observed in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; this variant was later reported to be a postzygotic mosaic mutation (Allele Fraction 0.38) in Lim et al., 2017.

Krishnan Probability Score

Score 0.59108066928544

Ranking 479/25841 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 1.9858054296518E-9

Ranking 16486/18225 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 0.95073152479735

Ranking 18607/18665 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
Larsen Cumulative Evidence Score

Score 9

Ranking 203/461 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.
Original Source
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