Human Gene Module / Chromosome 9 / PTCH1

PTCH1patched 1

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
10 / 15
Rare Variants / Common Variants
17 / 0
Aliases
-
Associated Syndromes
Basal cell nevus syndrome 1
Chromosome Band
9q22.32
Associated Disorders
-
Relevance to Autism

Trio-based whole-exome sequencing of 168 patients with low-functioning ASD at Sun Yat-sen Memorial Hospital in Wu et al., 2025 identified a paternally-inherited loss-of-function variant in the PTCH1 gene in a patient clinically diagnosed with ASD based on DSM-5 criteria and presenting with global developmental delay/intellectual disability. A number of de novo variants in PTCH1, including a de novo loss-of-function variant and several de novo missense variants that are predicted to be deleterious, have been identified in ASD probands from the Simons Simplex Collection, the SPARK cohort, the MSSNG cohort, the Autism Sequencing Consortium, the iHART cohort, and a Japanese cohort of 262 ASD probands (Iossifov et al., 2014; Yuen et al., 2016; Takata et al., 2018; Ruzzo et al., 2019; Zhou et al., 2022; Fu et al., 2022). Autism spectrum disorder or autistic traits have been reported in a subset of individuals with PTCH1-associated disorders, including basal cell nevus syndrome and somatic overgrowth with macrocephaly (Delbroek et al., 2011; Klein et al., 2019; Mashayekhi et al., 2023). Alterations in hippocampal and cortical layer structure, activity, and social behavior were observed in female Ptch1 +/- mice (Jackson et al., 2020). A prevalence estimate of autism of 4% was made in a cohort of 109 individuals from Norway with basal cell naevus syndrome caused by pathogenic PTCH1 variants (Brandtzg et al., 2025).

Molecular Function

This gene encodes a member of the patched family of proteins and a component of the hedgehog signaling pathway. Hedgehog signaling is important in embryonic development and tumorigenesis. The encoded protein is the receptor for the secreted hedgehog ligands, which include sonic hedgehog, indian hedgehog and desert hedgehog. Following binding by one of the hedgehog ligands, the encoded protein is trafficked away from the primary cilium, relieving inhibition of the G-protein-coupled receptor smoothened, which results in activation of downstream signaling. Mutations of this gene have been associated with basal cell nevus syndrome and holoprosencephaly.

External Links
Gene CardPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Reports related to PTCH1 (15 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Hanne Delbroek et al. (2011) No ASD
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support Genome-wide characteristics of de novo mutations in autism Yuen RK et al. (2016) Yes -
4 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
5 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
6 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
7 Support - Steven D Klein et al. (2019) No ASD
8 Support - Thomas W Jackson et al. (2020) No -
9 Support - Zhou X et al. (2022) Yes -
10 Support - Fu JM et al. (2022) Yes -
11 Support - More RP et al. (2023) Yes -
12 Support - Parisa Mashayekhi et al. (2023) No Autistic features
13 Support - Srividhya Durbagula et al. (2024) Yes -
14 Primary - Ruohao Wu et al. (2025) Yes -
15 Support - Karianne Haga Brandtzæg et al. () No ASD
Rare Variants   (17)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Unknown - - 31639285 Steven D Klein et al. (2019)
c.2448G>A p.Gln816= synonymous_variant De novo - - 35982160 Fu JM et al. (2022)
c.3713T>C p.Leu1238Pro missense_variant Unknown - - 28831199 Li J , et al. (2017)
c.3274A>G p.Ile1092Val missense_variant De novo - - 35982160 Fu JM et al. (2022)
c.654+1G>C p.? splice_site_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1972A>G p.Met658Val missense_variant De novo - Unknown 35982159 Zhou X et al. (2022)
c.842T>C p.Met281Thr missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.2847C>T p.Val949= synonymous_variant De novo - Simplex 27525107 Yuen RK et al. (2016)
c.2670C>G p.Thr890= synonymous_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.1405G>A p.Val469Met missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.716C>T p.Ala239Val missense_variant De novo - Multiplex 31398340 Ruzzo EK , et al. (2019)
c.2289C>T p.Val763= synonymous_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.654+1G>T p.? splice_site_variant De novo - Simplex 37752108 Parisa Mashayekhi et al. (2023)
c.884C>T p.Pro295Leu missense_variant Familial Maternal Multiplex 36702863 More RP et al. (2023)
c.3932del p.Leu1311CysfsTer61 frameshift_variant Familial Paternal - 41127290 Ruohao Wu et al. (2025)
c.4014_4034del21 p.Trp1339_Arg1345del inframe_deletion Unknown - - 31639285 Steven D Klein et al. (2019)
c.3940C>T p.Pro1314Ser missense_variant Familial Paternal Simplex 39534727 Srividhya Durbagula et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

criteria met
See SFARI Gene'scoring criteria
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.

10/1/2025
3

Initial score established: 3

Krishnan Probability Score

Score 0.56794733727959

Ranking 1149/25841 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 0.99999885730953

Ranking 310/18225 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 0.94983219573571

Ranking 18250/18665 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
Zhang D Score

Score -0.036790188397326

Ranking 9927/20870 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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