Human Gene Module / Chromosome 1 / PTBP2

PTBP2polypyrimidine tract binding protein 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 8
Rare Variants / Common Variants
5 / 1
Aliases
PTBP2, PTBLP,  brPTB,  nPTB
Associated Syndromes
-
Chromosome Band
1p21.3
Associated Disorders
-
Relevance to Autism

A previously unreported 5 bp indel variant located in a human accelerated region (HAR) between the DPYD and PTBP2 genes was homozygous in two brothers with ASD and ID from a consanguineous family; 4C-seq in human SH-SY5Y cell suggested an interaction between this HAR and the PTBP2 promoter, and luciferase reporter assays demonstrated that this indel variant reduced activity in N2A cells co-transfected with DN-REST and in primary mouse neurospheres (Doan et al., 2016). A de novo predicted damaging missense variant in PTBP2 was observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014).

Molecular Function

The protein encoded by this gene binds to intronic polypyrimidine clusters in pre-mRNA molecules and is implicated in controlling the assembly of other splicing-regulatory proteins. This protein is very similar to the polypyrimidine tract binding protein (PTB) but most of its isoforms are expressed primarily in the brain.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PTBP2 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Primary Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior Doan RN , et al. (2016) Yes -
4 Recent Recommendation Identification of common genetic risk variants for autism spectrum disorder Grove J , et al. (2019) Yes -
5 Support - Hildebrand MS et al. (2020) No ASD, ADHD, DD
6 Support - Woodbury-Smith M et al. (2022) Yes -
7 Recent Recommendation - Dawicki-McKenna JM et al. (2023) No -
8 Support - Salehi S et al. (2023) No -
Rare Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.9-11_9-10insAT - intron_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1150G>A p.Val384Met missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.3G>A p.Met1? initiator_codon_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.74G>C p.Arg25Thr missense_variant De novo - Simplex 32345733 Hildebrand MS et al. (2020)
TGGGTAC>TA - intergenic_variant Familial Both parents Multiplex 27667684 Doan RN , et al. (2016)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
A/AT - intergenic_variant - - - 30804558 Grove J , et al. (2019)
SFARI Gene score
2

Strong Candidate

A previously unreported 5 bp indel variant located in a human accelerated region (HAR) between the DPYD and PTBP2 genes was homozygous in two brothers with ASD and ID from a consanguineous family; 4C-seq in human SH-SY5Y cell suggested an interaction between this HAR and the PTBP2 promoter, and luciferase reporter assays demonstrated that this indel variant reduced activity in N2A cells co-transfected with DN-REST and in primary mouse neurospheres (Doan et al., 2016). A de novo predicted damaging missense variant in PTBP2 was observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). An intergenic SNP located approximately 625 kb from the PTBP2 gene was the index variant for a genome-wide significant locus (P = 2.48E-08) identified in a combined analysis of 18,381 ASD cases and 27,969 controls from iPSYCH and the Psychiatric Genomic Consortium (PGC) and five cohorts of European ancestry including a total of 2,119 additional ASD cases and 142,379 controls; PTBP2 was the nearest protein-coding gene from the index variant (Grove et al., 2019).

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 previously unreported 5 bp indel variant located in a human accelerated region (HAR) between the DPYD and PTBP2 genes was homozygous in two brothers with ASD and ID from a consanguineous family; 4C-seq in human SH-SY5Y cell suggested an interaction between this HAR and the PTBP2 promoter, and luciferase reporter assays demonstrated that this indel variant reduced activity in N2A cells co-transfected with DN-REST and in primary mouse neurospheres (Doan et al., 2016). A de novo predicted damaging missense variant in PTBP2 was observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). An intergenic SNP located approximately 625 kb from the PTBP2 gene was the index variant for a genome-wide significant locus (P = 2.48E-08) identified in a combined analysis of 18,381 ASD cases and 27,969 controls from iPSYCH and the Psychiatric Genomic Consortium (PGC) and five cohorts of European ancestry including a total of 2,119 additional ASD cases and 142,379 controls; PTBP2 was the nearest protein-coding gene from the index variant (Grove et al., 2019).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A previously unreported 5 bp indel variant located in a human accelerated region (HAR) between the DPYD and PTBP2 genes was homozygous in two brothers with ASD and ID from a consanguineous family; 4C-seq in human SH-SY5Y cell suggested an interaction between this HAR and the PTBP2 promoter, and luciferase reporter assays demonstrated that this indel variant reduced activity in N2A cells co-transfected with DN-REST and in primary mouse neurospheres (Doan et al., 2016). A de novo predicted damaging missense variant in PTBP2 was observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). An intergenic SNP located approximately 625 kb from the PTBP2 gene was the index variant for a genome-wide significant locus (P = 2.48E-08) identified in a combined analysis of 18,381 ASD cases and 27,969 controls from iPSYCH and the Psychiatric Genomic Consortium (PGC) and five cohorts of European ancestry including a total of 2,119 additional ASD cases and 142,379 controls; PTBP2 was the nearest protein-coding gene from the index variant (Grove et al., 2019).

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

Decreased from 4 to 4

Description

A previously unreported 5 bp indel variant located in a human accelerated region (HAR) between the DPYD and PTBP2 genes was homozygous in two brothers with ASD and ID from a consanguineous family; 4C-seq in human SH-SY5Y cell suggested an interaction between this HAR and the PTBP2 promoter, and luciferase reporter assays demonstrated that this indel variant reduced activity in N2A cells co-transfected with DN-REST and in primary mouse neurospheres (Doan et al., 2016). A de novo predicted damaging missense variant in PTBP2 was observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). An intergenic SNP located approximately 625 kb from the PTBP2 gene was the index variant for a genome-wide significant locus (P = 2.48E-08) identified in a combined analysis of 18,381 ASD cases and 27,969 controls from iPSYCH and the Psychiatric Genomic Consortium (PGC) and five cohorts of European ancestry including a total of 2,119 additional ASD cases and 142,379 controls; PTBP2 was the nearest protein-coding gene from the index variant (Grove et al., 2019).

Reports Added
[Identification of common genetic risk variants for autism spectrum disorder.2019]
10/1/2016
icon
4

Increased from to 4

Description

A previously unreported 5 bp indel variant located in a human accelerated region (HAR) between the DPYD and PTBP2 genes was homozygous in two brothers with ASD and ID from a consanguineous family; 4C-seq in human SH-SY5Y cell suggested an interaction between this HAR and the PTBP2 promoter, and luciferase reporter assays demonstrated that this indel variant reduced activity in N2A cells co-transfected with DN-REST and in primary mouse neurospheres (Doan et al., 2016). A de novo predicted damaging missense variant in PTBP2 was observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014).

Krishnan Probability Score

Score 0.51632098669334

Ranking 1750/25841 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 0.99269342922857

Ranking 1678/18225 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 0.71613067937631

Ranking 1266/18665 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 0.32136113663424

Ranking 2417/20870 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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