Human Gene Module / Chromosome 9 / PTPRD

PTPRDprotein tyrosine phosphatase receptor type D

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
8 / 14
Rare Variants / Common Variants
8 / 5
Aliases
-
Associated Syndromes
Restless leg syndrome
Chromosome Band
9p24.1-p23
Associated Disorders
-
Relevance to Autism

A window-based analysis of common and low-frequency genetic variation from 2,836 ASD trios from the MSSNG cohort with the summary statistics of the population-based meta-analysis from the iPSYCH project using KnockoffHybrid-Z, a statistical method for the analysis of trio and population data in genome-wide association studies, in Yang et al., 2024, identified PTPRD as a significant loci with a false discovery rate (FDR) at 0.1 (ATAC p-value 6.43E-07). Association of PTPRD with ASD had previously been shown in an East Asian case-control association study (Liu et al., 2016). A number of de novo variants in PTPRD, including a de novo loss-of-function variant and a missense variant with a REVEL score greater than 0.5, have been identified in ASD probands (Yuen et al., 2017; Zhou et al., 2022). A PTPRD missense variant was found to be shared by both ASD-affected siblings in a Spanish multiplex family in Toma et al., 2014. A maternally-inherited deletion affecting the PTPRD gene was reported in a male patient presenting with autism spectrum disorder, intellectual disability, and sleep disturbance in Servetti et al., 2021. Copy number variation affecting the PTPRD gene has also been observed in individuals with ADHD (Elia et al., 2010) and OCD (Gazzellone et al., 2016). A genome-wide association analysis (GWAS) of obsessive-compulsive (OC) traits using the Toronto Obsessive-Compulsive Scale (TOCS) in 5018 unrelated Caucasian children and adolescents from the community in Burton et al., 2021 found that an intronic SNP in PTPRD (rs7856850) was significantly associated with OC traits at the genome-wide significance level (p-value 2.48E-08); this polymorphism was also associated with OCD in a meta-analysis of OCD case/control genome-wide datasets (p = 0.0069). Association of this gene with restless leg syndrome has also been reported in a case-control association study (Schormair et al., 2008).

Molecular Function

The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains an extracellular region, a single transmembrane segment and two tandem intracytoplasmic catalytic domains, and thus represents a receptor-type PTP. The extracellular region of this protein is composed of three Ig-like and eight fibronectin type III-like domains. Studies of the similar genes in chicken and fly suggest the role of this PTP is in promoting neurite growth, and regulating neurons axon guidance. The protein encoded by the PTPRD gene can bidirectionally induce pre- and post-synaptic differentiation of neurons by mediating interaction with IL1RAP and IL1RAPL1 trans-synaptically. Loss of PTPRD was found to increase the number of neurogenic transit-amplifying intermediate progenitor cells and cort

External Links
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Human
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Mouse
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SFARI Genomic Platforms
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Reports related to PTPRD (14 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Positive Association - Barbara Schormair et al. (2008) No -
2 Support Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes Elia J , et al. (2009) No -
3 Support Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations Toma C , et al. (2013) Yes -
4 Positive Association Genome-wide Association Study of Autism Spectrum Disorder in the East Asian Populations Liu X , et al. (2015) Yes -
5 Support - Matthew J Gazzellone et al. (2016) No -
6 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
7 Support Both rare and common genetic variants contribute to autism in the Faroe Islands Leblond CS , et al. (2019) Yes -
8 Support - Hideaki Tomita et al. (2020) No -
9 Positive Association - Christie L Burton et al. (2021) No Obsessive-compulsive traits
10 Support - Martina Servetti et al. (2021) Yes -
11 Support - Zhou X et al. (2022) Yes -
12 Support - Francisca Cornejo et al. (2024) No -
13 Primary - Yi Yang et al. () Yes -
14 Support - Bastián I Cortés et al. (2024) Yes -
Rare Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Familial Paternal - 34621295 Martina Servetti et al. (2021)
c.551-5C>T - splice_region_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.780G>A p.Val260= synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1049C>G p.Pro350Arg missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.5548dup p.Thr1850AsnfsTer38 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.3299C>T p.Thr1100Met missense_variant Familial - Multiplex 23999528 Toma C , et al. (2013)
c.3855C>T p.Val1285= synonymous_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.3958C>T p.Arg1320Trp missense_variant Unknown - Unknown 30675382 Leblond CS , et al. (2019)
Common Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- - intergenic_variant - - - 38821058 Yi Yang et al. ()
- - intergenic_variant - - - 26314684 Liu X , et al. (2015)
c.353-17316G>T - intron_variant - - - 33531474 Christie L Burton et al. (2021)
c.-202-78374C>T - intron_variant - - - 18660810 Barbara Schormair et al. (2008)
c.-103-113009C>T - intron_variant - - - 18660810 Barbara Schormair et al. (2008)
SFARI Gene score
2

Strong Candidate

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.

7/1/2024
2

Initial score established: 2

Krishnan Probability Score

Score 0.60826114307299

Ranking 287/25841 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 0.9999999820376

Ranking 153/18225 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 0.95085695603483

Ranking 18655/18665 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 0.13517284209012

Ranking 5455/20870 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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