Human Gene Module / Chromosome X / PTCHD1

PTCHD1patched domain containing 1

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
7 / 11
Rare Variants / Common Variants
48 / 3
Aliases
PTCHD1, FLJ30296,  MGC149798,  PTCHD1
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Genetic Association
Chromosome Band
Xp22.11
Associated Disorders
ID
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).

Reports related to PTCHD1 (11 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 -
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 -
Rare Variants   (48)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Familial Maternal Multiplex 18252227 Marshall CR , et al. (2008)
- - copy_number_loss Familial Maternal Simplex 20531469 Pinto D , et al. (2010)
- - copy_number_loss Familial Maternal Multiplex 20531469 Pinto D , et al. (2010)
- - copy_number_loss Familial Maternal Multi-generational 20655035 Whibley AC , et al. (2010)
- - copy_number_loss Familial Maternal Multiplex 20844286 Noor A , et al. (2010)
- - copy_number_loss Familial Maternal Multi-generational 20844286 Noor A , et al. (2010)
c.517A>G p.Ile173Val missense_variant Familial Maternal Simplex 20844286 Noor A , et al. (2010)
c.[1008G>T; 1009C>A] p.[Met336Ile; 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.1409C>A p.Ala470Asp missense_variant Familial Maternal - 20844286 Noor A , et al. (2010)
c.1076A>G p.His359Arg missense_variant Familial Maternal Multiplex 20844286 Noor A , et al. (2010)
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)
- - copy_number_loss Familial Maternal Simplex 20844286 Noor A , et al. (2010)
- - copy_number_loss Familial Maternal Multiplex 20844286 Noor A , et al. (2010)
- - copy_number_loss Familial Maternal Simplex 20844286 Noor A , et al. (2010)
- - copy_number_loss Familial Maternal Multiplex 20844286 Noor A , et al. (2010)
- - copy_number_loss Familial Maternal Multiplex 20844286 Noor A , et al. (2010)
- - copy_number_loss Familial Maternal Multiplex 20844286 Noor A , et al. (2010)
- - copy_number_loss Familial Maternal Multiplex 20844286 Noor A , et al. (2010)
- - copy_number_loss Familial Maternal Multiplex 20844286 Noor A , et al. (2010)
- - copy_number_loss Familial Paternal Multi-generational 20844286 Noor A , et al. (2010)
- - copy_number_loss Familial Maternal Simplex 20844286 Noor A , et al. (2010)
- - copy_number_loss Familial Maternal Multiplex 21091464 Filges I , et al. (2010)
- - copy_number_loss Unknown - Unknown 23275889 Prasad A , et al. (2013)
c.2128delC p.Leu710CysfsTer12 frameshift_variant Familial Maternal Multi-generational 25131214 Chaudhry A , et al. (2014)
c.1796insA p.Asn599LysfsTer8 frameshift_variant Familial Maternal Multi-generational 25131214 Chaudhry A , et al. (2014)
c.1444delC p.Leu482TyrfsTer14 frameshift_variant Familial Maternal - 25131214 Chaudhry A , et al. (2014)
- - copy_number_loss Familial Maternal - 25131214 Chaudhry A , et al. (2014)
- - copy_number_loss Familial Maternal - 25131214 Chaudhry A , et al. (2014)
- - copy_number_loss Familial Maternal - 25131214 Chaudhry A , et al. (2014)
- - copy_number_loss Familial Maternal - 25131214 Chaudhry A , et al. (2014)
- - copy_number_loss Familial Maternal - 25131214 Chaudhry A , et al. (2014)
- - copy_number_loss De novo - - 25131214 Chaudhry A , et al. (2014)
- - copy_number_loss Familial Maternal - 25131214 Chaudhry A , et al. (2014)
- - copy_number_loss Familial Maternal - 25131214 Chaudhry A , et al. (2014)
- - copy_number_loss Familial Maternal - 25131214 Chaudhry A , et al. (2014)
- - copy_number_loss Familial Maternal - 25131214 Chaudhry A , et al. (2014)
c.2071C>T p.Arg691Ter stop_gained De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1443_1444delCCinsC p.Leu482TyrfsTer14 frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
- - 2KB_upstream_variant Unknown - Unknown 25782667 Torrico B , et al. (2015)
C>G - 2KB_upstream_variant Unknown - Unknown 25782667 Torrico B , et al. (2015)
c.152G>A p.Ser51Asn missense_variant Unknown - Unknown 25782667 Torrico B , et al. (2015)
A>C - intron_variant Unknown - Unknown 25782667 Torrico B , et al. (2015)
c.690G>A p.(=) synonymous_variant Unknown - Unknown 25782667 Torrico B , et al. (2015)
c.542A>C p.Lys181Thr missense_variant Familial Maternal Multiplex 26539891 Karaca E , et al. (2015)
T>G - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
Common Variants   (3)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.351+21539T>G - intron_variant - - - 25782667 Torrico B , et al. (2015)
c.351+21539T>G - intron_variant - - - 25782667 Torrico B , et al. (2015)
(GCC)14 - trinucleotide_repeat_microsatellite_feature, 2KB_upstream_variant - - - 25782667 Torrico B , et al. (2015)
SFARI Gene score
2

Strong Candidate

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.

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.

04-01-2017
2

Initial score established: 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.

CNVs associated with PTCHD1(1 CNVs)
Xp22.11 15 Deletion-Duplication 28  /  82
Animal Models associated with PTCHD1(5 Models)
PTCHD1_1_KO_HE Genetic
PTCHD1_1_KO_HE_amphetamine Rescue-Pharmaceutical
PTCHD1_1_KO_HE_EBIO Rescue-Pharmaceutical
PTCHD1_2_CKO_HE_SSTN Genetic
PTCHD1_3_CKO_HE Genetic
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