Human Gene Module / Chromosome X / PTCHD1

PTCHD1patched domain containing 1

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
13 / 23
Rare Variants / Common Variants
48 / 2
EAGLE Score
0.8
Limited Learn More
Aliases
PTCHD1, FLJ30296,  MGC149798,  PTCHD1
Associated Syndromes
-
Chromosome Band
Xp22.11
Associated Disorders
ID, ASD
Genetic Category
Rare Single Gene Mutation, Genetic Association, Functional
Relevance to Autism

Several studies have found rare single gene mutations, including deletions and missense mutations, in the PTCHD1 gene that have associations with autism. For example, Marshall et al. (2008) found a 160kb deletion that results in a null mutation for the PTCHD1 gene.

Molecular Function

PTCHD1 is suggested to be a transmembrane protein containing a patched-related domain with twelve transmembrane helices, highly related to the Hedgehog (Hh) receptors PATCHED1 (PTCH1) and PTCH2 as well as to Niemann-Pick Type C1 protein (NPC1).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome Informatics
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PTCHD1 (23 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Structural variation of chromosomes in autism spectrum disorder Marshall CR , et al. (2008) Yes -
2 Support Functional impact of global rare copy number variation in autism spectrum disorders Pinto D , et al. (2010) Yes -
3 Recent Recommendation Fine-scale survey of X chromosome copy number variants and indels underlying intellectual disability Whibley AC , et al. (2010) No -
4 Support Disruption at the PTCHD1 Locus on Xp22.11 in Autism spectrum disorder and intellectual disability Noor A , et al. (2010) Yes ID
5 Support Deletion in Xp22.11: PTCHD1 is a candidate gene for X-linked intellectual disability with or without autism Filges I , et al. (2010) No Autistic features
6 Support A discovery resource of rare copy number variations in individuals with autism spectrum disorder Prasad A , et al. (2013) Yes -
7 Recent Recommendation Phenotypic spectrum associated with PTCHD1 deletions and truncating mutations includes intellectual disability and autism spectrum disorder Chaudhry A , et al. (2014) Yes -
8 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
9 Positive Association Contribution of common and rare variants of the PTCHD1 gene to autism spectrum disorders and intellectual disability Torrico B , et al. (2015) Yes ID
10 Support Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease Karaca E , et al. (2015) No -
11 Support Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior Doan RN , et al. (2016) Yes -
12 Support - Brunet T et al. (2021) No -
13 Support - Halewa J et al. (2021) No ASD, ID
14 Support - Gerges P et al. (2022) Yes -
15 Support - Zhou X et al. (2022) Yes -
16 Support - Mona Abdi et al. (2023) Yes -
17 Support - Stephen F Pastore et al. (2023) No -
18 Support - Kathryn O Farley et al. (2024) No Autistic behavior
19 Support - Omri Bar et al. (2024) Yes ADD, OCD, ID
20 Support - Connie T Y Xie et al. (2024) Yes ID
21 Support - Federica Alice Maria Montanaro et al. (2024) No ASD
22 Support - Marketa Wayhelova et al. (2024) No -
23 Support - Laura E Burnett et al. () Yes -
Rare Variants   (48)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 25131214 Chaudhry A , et al. (2014)
T>G - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
- - copy_number_loss Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_loss Familial Maternal - 25131214 Chaudhry A , et al. (2014)
- - 2KB_upstream_variant Unknown - Unknown 25782667 Torrico B , et al. (2015)
- - copy_number_loss Familial Maternal Simplex 20844286 Noor A , et al. (2010)
- - copy_number_loss Familial Maternal Simplex 20531469 Pinto D , et al. (2010)
c.986T>C p.Phe329Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial Maternal Multiplex 20844286 Noor A , et al. (2010)
c.352-4A>C - intron_variant Unknown - Unknown 25782667 Torrico B , et al. (2015)
- - copy_number_loss Familial Maternal Multiplex 20531469 Pinto D , et al. (2010)
c.928G>C p.Ala310Pro missense_variant De novo - - 33856728 Halewa J et al. (2021)
- - copy_number_loss Familial Maternal Multiplex 21091464 Filges I , et al. (2010)
- - copy_number_loss Familial Maternal Multiplex 25131214 Chaudhry A , et al. (2014)
- - copy_number_loss Familial Maternal Multiplex 18252227 Marshall CR , et al. (2008)
- - copy_number_loss Familial Maternal Multi-generational 20844286 Noor A , et al. (2010)
- - copy_number_loss Familial Paternal Multi-generational 20844286 Noor A , et al. (2010)
c.95C>G p.Pro32Arg missense_variant Familial Maternal - 33856728 Halewa J et al. (2021)
c.95C>T p.Pro32Leu missense_variant Familial Maternal - 33856728 Halewa J et al. (2021)
c.1804A>G p.Thr602Ala missense_variant Unknown - Simplex 35205231 Gerges P et al. (2022)
c.152G>A p.Ser51Asn missense_variant Unknown - Unknown 25782667 Torrico B , et al. (2015)
c.1409C>A p.Ala470Asp missense_variant Familial Maternal - 20844286 Noor A , et al. (2010)
c.638A>G p.Tyr213Cys missense_variant Familial Maternal - 33856728 Halewa J et al. (2021)
c.898G>C p.Gly300Arg missense_variant Familial Maternal - 33856728 Halewa J et al. (2021)
c.690G>A p.Glu230= synonymous_variant Unknown - Unknown 25782667 Torrico B , et al. (2015)
- - copy_number_loss Familial Maternal Multi-generational 20655035 Whibley AC , et al. (2010)
- - copy_number_loss Familial Maternal Multi-generational 25131214 Chaudhry A , et al. (2014)
c.517A>G p.Ile173Val missense_variant Familial Maternal Simplex 20844286 Noor A , et al. (2010)
c.583G>A p.Val195Ile missense_variant Familial Maternal Simplex 20844286 Noor A , et al. (2010)
c.1008G>T p.Met336Ile missense_variant Familial Maternal Simplex 20844286 Noor A , et al. (2010)
c.1009C>A p.Leu337Ile missense_variant Familial Maternal Simplex 20844286 Noor A , et al. (2010)
c.1436A>G p.Glu479Gly missense_variant Familial Maternal Simplex 20844286 Noor A , et al. (2010)
c.217C>T p.Leu73Phe missense_variant Familial Maternal Multiplex 20844286 Noor A , et al. (2010)
c.852C>G p.Ile284Met missense_variant Familial Maternal Simplex 38256266 Omri Bar et al. (2024)
c.134G>A p.Arg45His missense_variant Familial Maternal Simplex 37805537 Mona Abdi et al. (2023)
c.113T>A p.Leu38Gln missense_variant Familial Maternal Multiplex 33619735 Brunet T et al. (2021)
c.1076A>G p.His359Arg missense_variant Familial Maternal Multiplex 20844286 Noor A , et al. (2010)
c.542A>C p.Lys181Thr missense_variant Familial Maternal Multiplex 26539891 Karaca E , et al. (2015)
- - copy_number_loss Familial Maternal Simplex 38288059 Federica Alice Maria Montanaro et al. (2024)
c.2489T>G p.Ile830Arg missense_variant Unknown Not maternal - 38007613 Kathryn O Farley et al. (2024)
c.1444del p.Leu482TyrfsTer14 frameshift_variant Familial Maternal - 25131214 Chaudhry A , et al. (2014)
c.224C>A p.Pro75Gln missense_variant Familial Maternal Multiplex 38275824 Connie T Y Xie et al. (2024)
c.1765G>T p.Glu589Ter stop_gained Familial Maternal Multiplex 38321498 Marketa Wayhelova et al. (2024)
c.2071C>T p.Arg691Ter stop_gained De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1796dup p.Asn599LysfsTer8 frameshift_variant Familial Maternal Multi-generational 25131214 Chaudhry A , et al. (2014)
c.2128del p.Leu710CysfsTer13 frameshift_variant Familial Maternal Multi-generational 25131214 Chaudhry A , et al. (2014)
c.1444del p.Leu482TyrfsTer14 frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1877T>C p.Phe626Ser missense_variant Familial Maternal Extended multiplex 38288059 Federica Alice Maria Montanaro et al. (2024)
Common Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
(GCC)14 - trinucleotide_repeat_microsatellite_feature, 2KB_upstream_variant - - - 25782667 Torrico B , et al. (2015)
c.351+21539T>G - intron_variant - - - 25782667 Torrico B , et al. (2015)
SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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.

4/1/2021
1
icon
1

Score remained at 1

Description

There is strong evidence for the role of PTCHD1, an X-linked gene, in autism, based on the finding of deletions and mutations disrupting the gene in affected individuals but not in controls (see Noor et al. ,2010, Marshall et al., 2008, Pinto et al., 2010). These reports include a deletion transmitted from an unaffected mother with skewed X inactivation to 2 affected twin sons and an unaffected daughter. There is also a deletion in 1/246 males in an intellectual disability cohort. Sequence analysis in 723 male ASD, 177 female ASD, and 225 male cases of intellectual disability revealed 7 missense mutations in 8 cases. These same changes were not seen in 700 controls (p=0.042 enrichment case v ctrl). Deletions upstream of PTCHD1 were also reported in 8/996 ASD probands, but none in 4829 male controls.

Reports Added
[Novel missense mutations in PTCHD1 alter its plasma membrane subcellular localization and cause intellectual disability and autism spectrum disorder2021]
1/1/2021
1
icon
1

Score remained at 1

Description

There is strong evidence for the role of PTCHD1, an X-linked gene, in autism, based on the finding of deletions and mutations disrupting the gene in affected individuals but not in controls (see Noor et al. ,2010, Marshall et al., 2008, Pinto et al., 2010). These reports include a deletion transmitted from an unaffected mother with skewed X inactivation to 2 affected twin sons and an unaffected daughter. There is also a deletion in 1/246 males in an intellectual disability cohort. Sequence analysis in 723 male ASD, 177 female ASD, and 225 male cases of intellectual disability revealed 7 missense mutations in 8 cases. These same changes were not seen in 700 controls (p=0.042 enrichment case v ctrl). Deletions upstream of PTCHD1 were also reported in 8/996 ASD probands, but none in 4829 male controls.

Reports Added
[De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021]
10/1/2019
2
icon
1

Decreased from 2 to 1

New Scoring Scheme
Description

There is strong evidence for the role of PTCHD1, an X-linked gene, in autism, based on the finding of deletions and mutations disrupting the gene in affected individuals but not in controls (see Noor et al. ,2010, Marshall et al., 2008, Pinto et al., 2010). These reports include a deletion transmitted from an unaffected mother with skewed X inactivation to 2 affected twin sons and an unaffected daughter. There is also a deletion in 1/246 males in an intellectual disability cohort. Sequence analysis in 723 male ASD, 177 female ASD, and 225 male cases of intellectual disability revealed 7 missense mutations in 8 cases. These same changes were not seen in 700 controls (p=0.042 enrichment case v ctrl). Deletions upstream of PTCHD1 were also reported in 8/996 ASD probands, but none in 4829 male controls.

Reports Added
[New Scoring Scheme]
10/1/2016
2
icon
2

Decreased from 2 to 2

Description

There is strong evidence for the role of PTCHD1, an X-linked gene, in autism, based on the finding of deletions and mutations disrupting the gene in affected individuals but not in controls (see Noor et al. ,2010, Marshall et al., 2008, Pinto et al., 2010). These reports include a deletion transmitted from an unaffected mother with skewed X inactivation to 2 affected twin sons and an unaffected daughter. There is also a deletion in 1/246 males in an intellectual disability cohort. Sequence analysis in 723 male ASD, 177 female ASD, and 225 male cases of intellectual disability revealed 7 missense mutations in 8 cases. These same changes were not seen in 700 controls (p=0.042 enrichment case v ctrl). Deletions upstream of PTCHD1 were also reported in 8/996 ASD probands, but none in 4829 male controls.

Reports Added
[Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.2016]
1/1/2016
2
icon
2

Decreased from 2 to 2

Description

There is strong evidence for the role of PTCHD1, an X-linked gene, in autism, based on the finding of deletions and mutations disrupting the gene in affected individuals but not in controls (see Noor et al. ,2010, Marshall et al., 2008, Pinto et al., 2010). These reports include a deletion transmitted from an unaffected mother with skewed X inactivation to 2 affected twin sons and an unaffected daughter. There is also a deletion in 1/246 males in an intellectual disability cohort. Sequence analysis in 723 male ASD, 177 female ASD, and 225 male cases of intellectual disability revealed 7 missense mutations in 8 cases. These same changes were not seen in 700 controls (p=0.042 enrichment case v ctrl). Deletions upstream of PTCHD1 were also reported in 8/996 ASD probands, but none in 4829 male controls.

Reports Added
[Structural variation of chromosomes in autism spectrum disorder.2008] [Functional impact of global rare copy number variation in autism spectrum disorders.2010] [Disruption at the PTCHD1 Locus on Xp22.11 in Autism spectrum disorder and intellectual disability.2010] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Phenotypic spectrum associated with PTCHD1 deletions and truncating mutations includes intellectual disability and autism spectrum disorder.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Deletion in Xp22.11: PTCHD1 is a candidate gene for X-linked intellectual disability with or without autism.2010] [Fine-scale survey of X chromosome copy number variants and indels underlying intellectual disability.2010] [Contribution of common and rare variants of the PTCHD1 gene to autism spectrum disorders and intellectual disability.2015] [Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.2015]
4/1/2015
2
icon
2

Decreased from 2 to 2

Description

There is strong evidence for the role of PTCHD1, an X-linked gene, in autism, based on the finding of deletions and mutations disrupting the gene in affected individuals but not in controls (see Noor et al. ,2010, Marshall et al., 2008, Pinto et al., 2010). These reports include a deletion transmitted from an unaffected mother with skewed X inactivation to 2 affected twin sons and an unaffected daughter. There is also a deletion in 1/246 males in an intellectual disability cohort. Sequence analysis in 723 male ASD, 177 female ASD, and 225 male cases of intellectual disability revealed 7 missense mutations in 8 cases. These same changes were not seen in 700 controls (p=0.042 enrichment case v ctrl). Deletions upstream of PTCHD1 were also reported in 8/996 ASD probands, but none in 4829 male controls.

Reports Added
[Contribution of common and rare variants of the PTCHD1 gene to autism spectrum disorders and intellectual disability.2015]
1/1/2015
2
icon
2

Decreased from 2 to 2

Description

There is strong evidence for the role of PTCHD1, an X-linked gene, in autism, based on the finding of deletions and mutations disrupting the gene in affected individuals but not in controls (see Noor et al. ,2010, Marshall et al., 2008, Pinto et al., 2010). These reports include a deletion transmitted from an unaffected mother with skewed X inactivation to 2 affected twin sons and an unaffected daughter. There is also a deletion in 1/246 males in an intellectual disability cohort. Sequence analysis in 723 male ASD, 177 female ASD, and 225 male cases of intellectual disability revealed 7 missense mutations in 8 cases. These same changes were not seen in 700 controls (p=0.042 enrichment case v ctrl). Deletions upstream of PTCHD1 were also reported in 8/996 ASD probands, but none in 4829 male controls.

Reports Added
[Large-scale discovery of novel genetic causes of developmental disorders.2014]
7/1/2014
No data
icon
2

Increased from No data to 2

Description

There is strong evidence for the role of PTCHD1, an X-linked gene, in autism, based on the finding of deletions and mutations disrupting the gene in affected individuals but not in controls (see Noor et al. ,2010, Marshall et al., 2008, Pinto et al., 2010). These reports include a deletion transmitted from an unaffected mother with skewed X inactivation to 2 affected twin sons and an unaffected daughter. There is also a deletion in 1/246 males in an intellectual disability cohort. Sequence analysis in 723 male ASD, 177 female ASD, and 225 male cases of intellectual disability revealed 7 missense mutations in 8 cases. These same changes were not seen in 700 controls (p=0.042 enrichment case v ctrl). Deletions upstream of PTCHD1 were also reported in 8/996 ASD probands, but none in 4829 male controls.

Reports Added
[Structural variation of chromosomes in autism spectrum disorder.2008] [Functional impact of global rare copy number variation in autism spectrum disorders.2010] [Fine-scale survey of X chromosome copy number variants and indels underlying intellectual disability.2010] [Disruption at the PTCHD1 Locus on Xp22.11 in Autism spectrum disorder and intellectual disability.2010] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Phenotypic spectrum associated with PTCHD1 deletions and truncating mutations includes intellectual disability and autism spectrum disorder.2014] [Deletion in Xp22.11: PTCHD1 is a candidate gene for X-linked intellectual disability with or without autism.2010]
4/1/2014
No data
icon
2

Increased from No data to 2

Description

There is strong evidence for the role of PTCHD1, an X-linked gene, in autism, based on the finding of deletions and mutations disrupting the gene in affected individuals but not in controls (see Noor et al. ,2010, Marshall et al., 2008, Pinto et al., 2010). These reports include a deletion transmitted from an unaffected mother with skewed X inactivation to 2 affected twin sons and an unaffected daughter. There is also a deletion in 1/246 males in an intellectual disability cohort. Sequence analysis in 723 male ASD, 177 female ASD, and 225 male cases of intellectual disability revealed 7 missense mutations in 8 cases. These same changes were not seen in 700 controls (p=0.042 enrichment case v ctrl). Deletions upstream of PTCHD1 were also reported in 8/996 ASD probands, but none in 4829 male controls.

Krishnan Probability Score

Score 0.49643212954265

Ranking 2601/25841 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 0.94705307870957

Ranking 2730/18225 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 0.94006252689679

Ranking 14432/18665 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 45

Ranking 42/461 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 0.18202098061414

Ranking 4562/20870 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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