Human Gene Module / Chromosome 10 / PCDH15

PCDH15protocadherin related 15

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
9 / 12
Rare Variants / Common Variants
40 / 1
Aliases
PCDH15, RP11-449J3.2,  CDHR15,  DFNB23,  USH1F
Associated Syndromes
Usher syndrome, type 1F
Chromosome Band
10q21.1
Associated Disorders
-
Relevance to Autism

A SNP within the PCDH15 gene showed association in the secondary analyses in a combined AGP GWA sample (Anney et al., 2012).

Molecular Function

This gene is a member of the cadherin superfamily. Family members encode integral membrane proteins that mediate calcium-dependent cell-cell adhesion. It plays an essential role in maintenance of normal retinal and cochlear function. Mutations in this gene result in hearing loss and Usher Syndrome Type IF (USH1F).

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PCDH15 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Individual common variants exert weak effects on the risk for autism spectrum disorders Anney R , et al. (2012) Yes -
2 Support A discovery resource of rare copy number variations in individuals with autism spectrum disorder Prasad A , et al. (2013) Yes -
3 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
4 Support Investigation of Rare Single-Nucleotide PCDH15 Variants in Schizophrenia and Autism Spectrum Disorders Ishizuka K , et al. (2016) Yes -
5 Support Diagnostic Yields of Trio-WES Accompanied by CNVseq for Rare Neurodevelopmental Disorders Gao C , et al. (2019) No -
6 Support Genome-wide detection of tandem DNA repeats that are expanded in autism Trost B et al. (2020) Yes -
7 Support - Bruno LP et al. (2021) No -
8 Support - Woodbury-Smith M et al. (2022) Yes -
9 Support - N.Y.) (07/2) Yes -
10 Support - Zhou X et al. (2022) Yes -
11 Support - Cirnigliaro M et al. (2023) Yes -
12 Support - Daisuke Mori et al. (2024) No -
Rare Variants   (40)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - missense_variant Unknown - - 27058588 Ishizuka K , et al. (2016)
- - copy_number_loss Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - frameshift_variant De novo - Simplex 34948243 Bruno LP et al. (2021)
c.3979G>A p.Asp1327Asn missense_variant De novo - - 35901164 N.Y.) (07/2)
c.5467A>C p.Thr1823Pro missense_variant De novo - - 35901164 N.Y.) (07/2)
T>G p.Ser399Arg missense_variant Unknown - - 27058588 Ishizuka K , et al. (2016)
c.2138A>G p.Asn713Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
C>A p.Asp1237Tyr missense_variant Unknown - - 27058588 Ishizuka K , et al. (2016)
c.1del p.Met1? inframe_deletion Familial Maternal - 31178897 Gao C , et al. (2019)
c.3723C>T p.Ala1241%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.944C>T p.Pro315Leu missense_variant Unknown - - 27058588 Ishizuka K , et al. (2016)
c.1483G>A p.Val495Ile missense_variant Unknown - - 27058588 Ishizuka K , et al. (2016)
c.2884C>T p.Arg962Cys missense_variant Unknown - - 27058588 Ishizuka K , et al. (2016)
c.3451G>A p.Gly1151Arg missense_variant Unknown - - 27058588 Ishizuka K , et al. (2016)
C>T p.Asp642Asn missense_variant Unknown - Simplex 27058588 Ishizuka K , et al. (2016)
c.4987C>G p.Leu1663Val missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.146T>C p.Val49Ala missense_variant De novo - - 35205252 Woodbury-Smith M et al. (2022)
T>C p.Ile1185Met missense_variant Familial Paternal - 27058588 Ishizuka K , et al. (2016)
c.5844C>T p.Val1948%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.387A>G p.Lys129= missense_variant Familial Maternal - 27058588 Ishizuka K , et al. (2016)
c.3278G>A p.Gly1093Glu missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2940T>C p.Pro980= missense_variant Familial Maternal - 27058588 Ishizuka K , et al. (2016)
c.944C>T p.Pro315Leu missense_variant Familial Maternal - 27058588 Ishizuka K , et al. (2016)
c.959C>T p.Pro320Leu missense_variant Familial Paternal - 27058588 Ishizuka K , et al. (2016)
c.2884C>T p.Arg962Cys missense_variant Familial Paternal - 27058588 Ishizuka K , et al. (2016)
c.3451G>A p.Gly1151Arg missense_variant Familial Maternal - 27058588 Ishizuka K , et al. (2016)
c.3451G>A p.Gly1151Arg missense_variant Familial Paternal - 27058588 Ishizuka K , et al. (2016)
c.3466G>A p.Gly1156Arg missense_variant Familial Maternal - 27058588 Ishizuka K , et al. (2016)
C>T p.Arg219Lys missense_variant Familial Maternal Simplex 27058588 Ishizuka K , et al. (2016)
c.3010-1G>C - splice_site_variant Familial Maternal Simplex 27058588 Ishizuka K , et al. (2016)
C>T p.Met60Ile missense_variant Familial Paternal Multiplex 27058588 Ishizuka K , et al. (2016)
- - tetranucleotide_repeat_microsatellite_feature Unknown - Simplex 32717741 Trost B et al. (2020)
A>G p.Val469Ala missense_variant Familial Maternal Multiplex 27058588 Ishizuka K , et al. (2016)
T>C p.Thr281Ala missense_variant Familial Maternal Multiplex 27058588 Ishizuka K , et al. (2016)
c.748C>T p.Arg250Ter stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.4332_4337dup p.Pro1447_Pro1448dup inframe_indel Familial Paternal - 31178897 Gao C , et al. (2019)
c.5042T>A p.Leu1681Ter stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.721-3_732del - splice_site_variant Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.4705_4706insAAGT p.Ser1569Ter stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.228_229insC p.Thr77HisfsTer9 frameshift_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.92-13768C>T;c.92-14293C>T;c.91+122002C>T - intron_variant - - - 22843504 Anney R , et al. (2012)
SFARI Gene score
2

Strong Candidate

A SNP within the PCDH15 gene showed association with ASD in the secondary analyses in a combined AGP genome-wide association sample with a P-value of 9.861E08 (PMID 22843504). A de novo predicted damaging missense variant in PCDH15 was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). Rare inherited variants in PCDH15 were identified in Japanese ASD and schizophrenia cases, including a maternally-inherited splice-site variant identified in one ASD proband and a maternally-inherited missense variant observed in two brothers with ASD and ADHD (Ishizuka et al., 2016).

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

A SNP within the PCDH15 gene showed association with ASD in the secondary analyses in a combined AGP genome-wide association sample with a P-value of 9.861E08 (PMID 22843504). A de novo predicted damaging missense variant in PCDH15 was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). Rare inherited variants in PCDH15 were identified in Japanese ASD and schizophrenia cases, including a maternally-inherited splice-site variant identified in one ASD proband and a maternally-inherited missense variant observed in two brothers with ASD and ADHD (Ishizuka et al., 2016).

7/1/2020
3
icon
3

Decreased from 3 to 3

Description

A SNP within the PCDH15 gene showed association with ASD in the secondary analyses in a combined AGP genome-wide association sample with a P-value of 9.861E08 (PMID 22843504). A de novo predicted damaging missense variant in PCDH15 was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). Rare inherited variants in PCDH15 were identified in Japanese ASD and schizophrenia cases, including a maternally-inherited splice-site variant identified in one ASD proband and a maternally-inherited missense variant observed in two brothers with ASD and ADHD (Ishizuka et al., 2016).

Reports Added
[Genome-wide detection of tandem DNA repeats that are expanded in autism2020]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A SNP within the PCDH15 gene showed association with ASD in the secondary analyses in a combined AGP genome-wide association sample with a P-value of 9.861E08 (PMID 22843504). A de novo predicted damaging missense variant in PCDH15 was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). Rare inherited variants in PCDH15 were identified in Japanese ASD and schizophrenia cases, including a maternally-inherited splice-site variant identified in one ASD proband and a maternally-inherited missense variant observed in two brothers with ASD and ADHD (Ishizuka et al., 2016).

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

Decreased from 4 to 4

Description

A SNP within the PCDH15 gene showed association with ASD in the secondary analyses in a combined AGP genome-wide association sample with a P-value of 9.861E08 (PMID 22843504). A de novo predicted damaging missense variant in PCDH15 was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). Rare inherited variants in PCDH15 were identified in Japanese ASD and schizophrenia cases, including a maternally-inherited splice-site variant identified in one ASD proband and a maternally-inherited missense variant observed in two brothers with ASD and ADHD (Ishizuka et al., 2016).

Reports Added
[Diagnostic Yields of Trio-WES Accompanied by CNVseq for Rare Neurodevelopmental Disorders.2019]
4/1/2016
4
icon
4

Decreased from 4 to 4

Description

A SNP within the PCDH15 gene showed association with ASD in the secondary analyses in a combined AGP genome-wide association sample with a P-value of 9.861E?08 (PMID 22843504). A de novo predicted damaging missense variant in PCDH15 was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). Rare inherited variants in PCDH15 were identified in Japanese ASD and schizophrenia cases, including a maternally-inherited splice-site variant identified in one ASD proband and a maternally-inherited missense variant observed in two brothers with ASD and ADHD (Ishizuka et al., 2016).

Reports Added
[Individual common variants exert weak effects on the risk for autism spectrum disorderspi.2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Investigation of Rare Single-Nucleotide PCDH15 Variants in Schizophrenia and Autism Spectrum Disorders.2016]
1/1/2016
4
icon
4

Decreased from 4 to 4

Description

A SNP within the PCDH15 gene showed association in the secondary analyses in a combined AGP GWA sample with a P-value of 9.861E?08 (PMID 22843504).

Reports Added
[Individual common variants exert weak effects on the risk for autism spectrum disorderspi.2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [The contribution of de novo coding mutations to autism spectrum disorder2014]
7/1/2015
icon
4

Increased from to 4

Description

A SNP within the PCDH15 gene showed association in the secondary analyses in a combined AGP GWA sample with a P-value of 9.861E?08 (PMID 22843504).

Krishnan Probability Score

Score 0.46099699049277

Ranking 9421/25841 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 7.2312361289786E-11

Ranking 16969/18225 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 0.94224361547914

Ranking 15233/18665 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 3

Ranking 351/461 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
Zhang D Score

Score -0.087100241928202

Ranking 11842/20870 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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