Human Gene Module / Chromosome 9 / PAX5

PAX5Paired box 5

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
10 / 10
Rare Variants / Common Variants
23 / 0
EAGLE Score
5.75
Limited Learn More
Aliases
PAX5, ALL3,  BSAP
Associated Syndromes
-
Chromosome Band
9p13.2
Associated Disorders
-
Genetic Category
Rare Single Gene Mutation
Relevance to Autism

De novo loss-of-function variants in the PAX5 gene have been identified in two simplex ASD cases (Iossifov et al., 2014; O'Roak et al., 2014). A de novo likely damaging missense variant in PAX5 was identified in an ASD proband from the SPARK cohort (Feliciano et al., 2019); in the same report, a meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified PAX5 as an ASD candidate gene with a q-value 0.1.

Molecular Function

May play an important role in B-cell differentiation as well as neural development and spermatogenesis.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PAX5 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De novo gene disruptions in children on the autistic spectrum Iossifov I , et al. (2012) Yes -
2 Recent Recommendation Recurrent de novo mutations implicate novel genes underlying simplex autism risk O'Roak BJ , et al. (2014) Yes -
3 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
4 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
5 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
6 Recent Recommendation Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
7 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
8 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
9 Recent Recommendation - Gofin Y et al. (2022) Yes ADHD, epilepsy/seizures
10 Recent Recommendation - Kaiser FMP et al. (2022) Yes -
Rare Variants   (23)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 35094443 Gofin Y et al. (2022)
- - copy_number_loss Unknown - - 35094443 Gofin Y et al. (2022)
- - copy_number_loss Unknown - Multiplex 35094443 Gofin Y et al. (2022)
c.1129C>T p.Arg377Ter stop_gained Unknown - - 35094443 Gofin Y et al. (2022)
c.176G>A p.Arg59Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.662G>A p.Arg221Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.868G>A p.Gly290Arg missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3G>A p.Met1? initiator_codon_variant Unknown - - 33004838 Wang T et al. (2020)
c.419G>A p.Arg140Gln missense_variant De novo - - 35094443 Gofin Y et al. (2022)
c.661C>T p.Arg221Trp missense_variant De novo - - 35094443 Gofin Y et al. (2022)
c.338A>T p.Glu113Val missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.724G>T p.Glu242Ter stop_gained De novo - Simplex 35947077 Kaiser FMP et al. (2022)
c.46G>C p.Gly16Arg missense_variant De novo - Simplex 25418537 O'Roak BJ , et al. (2014)
c.962C>A p.Pro321His missense_variant Unknown - Multiplex 35094443 Gofin Y et al. (2022)
c.997G>A XP_005251537.1:p.Gly333Arg missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1085G>A XP_005251537.1:p.Gly362Glu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.385G>A p.Val129Met missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.76dup p.Val26GlyfsTer49 frameshift_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.157G>C p.Asp53His missense_variant Familial Maternal Multiplex 35094443 Gofin Y et al. (2022)
c.92G>A p.Arg31Gln missense_variant Familial Maternal Simplex 35947077 Kaiser FMP et al. (2022)
c.76dup p.Val26GlyfsTer49 frameshift_variant De novo - Simplex 25418537 O'Roak BJ , et al. (2014)
c.333del p.Trp112GlyfsTer47 frameshift_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.76dup p.Val26GlyfsTer49 frameshift_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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
2
icon
1

Decreased from 2 to 1

10/1/2020
2
icon
2

Decreased from 2 to 2

Description

Two de novo likely gene-disruptive variants and one de novo missense variant in the PAX5 gene have been identified in independent simplex cohorts (PMID 22542183, 25418537). An additional de novo likely gene-disruptive variant in the PAX5 gene was identified in an ASD proband from the SPARK cohort in Feliciano et al., 2019; in the same report, meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified PAX5 as an ASD candidate gene with a q-value 0.1.

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
1/1/2020
2
icon
2

Decreased from 2 to 2

Description

Two de novo likely gene-disruptive variants and one de novo missense variant in the PAX5 gene have been identified in independent simplex cohorts (PMID 22542183, 25418537). An additional de novo likely gene-disruptive variant in the PAX5 gene was identified in an ASD proband from the SPARK cohort in Feliciano et al., 2019; in the same report, meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified PAX5 as an ASD candidate gene with a q-value 0.1.

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Two de novo likely gene-disruptive variants and one de novo missense variant in the PAX5 gene have been identified in independent simplex cohorts (PMID 22542183, 25418537). An additional de novo likely gene-disruptive variant in the PAX5 gene was identified in an ASD proband from the SPARK cohort in Feliciano et al., 2019; in the same report, meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified PAX5 as an ASD candidate gene with a q-value 0.1.

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
1/1/2019
3
icon
3

Decreased from 3 to 3

Description

Two de novo LoF variants and one de novo missense variant in the PAX5 gene have been identified in independent simplex cohorts (PMID 22542183, 25418537).

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
4/1/2017
3
icon
3

Decreased from 3 to 3

Description

Two de novo LoF variants and one de novo missense variant in the PAX5 gene have been identified in independent simplex cohorts (PMID 22542183, 25418537).

Reports Added
[De novo gene disruptions in children on the autistic spectrum.2012] [Recurrent de novo mutations implicate novel genes underlying simplex autism risk.2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017]
1/1/2016
3
icon
3

Decreased from 3 to 3

Description

Two de novo LoF variants and one de novo missense variant in the PAX5 gene have been identified in independent simplex cohorts (PMID 22542183, 25418537).

Reports Added
[De novo gene disruptions in children on the autistic spectrum.2012] [Recurrent de novo mutations implicate novel genes underlying simplex autism risk.2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
10/1/2014
icon
3

Increased from to 3

Description

Two de novo LoF variants and one de novo missense variant in the PAX5 gene have been identified in independent simplex cohorts (PMID 22542183, 25418537).

Krishnan Probability Score

Score 0.49402694853886

Ranking 3863/25841 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 0.98424398873027

Ranking 2009/18225 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
Iossifov Probability Score

Score 0.812

Ranking 225/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.45455840801665

Ranking 360/18665 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
Larsen Cumulative Evidence Score

Score 19

Ranking 109/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score -0.16692564529118

Ranking 14617/20870 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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