Human Gene Module / Chromosome 1 / PTBP2

PTBP2polypyrimidine tract binding protein 2

Score
4
Minimal Evidence Criteria 4.1
Autism Reports / Total Reports
3 / 3
Rare Variants / Common Variants
3 / 0
Aliases
PTBP2, PTBLP,  brPTB,  nPTB
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
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.

Reports related to PTBP2 (3 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 -
Rare Variants   (3)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1150G>A p.Asp384Asn missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
insTA - intron_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
TGGGTAC>TA - intergenic_variant;intergenic_variant Familial Both parents Multiplex 27667684 Doan RN , et al. (2016)
Common Variants  

No common variants reported.

SFARI Gene score
4

Minimal Evidence

4

Score Delta: Score remained at 4.4

4

Minimal Evidence

See all Category 4 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.

10/1/2016
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.
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
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).
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.
CNVs associated with PTBP2(1 CNVs)
1p21.3 13 Deletion-Duplication 24  /  54
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