Human Gene Module / Chromosome 1 / PBX1

PBX1PBX homeobox 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 9
Rare Variants / Common Variants
16 / 0
Aliases
PBX1, CAKUHED
Associated Syndromes
-
Chromosome Band
1q23.3
Associated Disorders
-
Relevance to Autism

A de novo likely gene disruptive (LGD) variant and two de novo missense variants in the PBX1 gene were identified in ASD probands (De Rubeis et al., 2014; Yuen et al., 2017), while two additional de novo missense variants in this gene were identified in probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified PBX1 as a gene with an excess of missense variants (false discovery rata < 5%, count >1) (Coe et al., 2018). Two de novo loss-of-function variants and two rare and potentially damaging missense variants in the PBX1 gene were reported in ASD probands from the Autism Sequencing Consortium and the SPARK cohort in Zhou et al., 2022; a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in this report identified PBX1 as a gene reaching study-wide significance based on 5,754 constraint genes (P < 8.69E-06).

Molecular Function

This gene encodes a nuclear protein that belongs to the PBX homeobox family of transcriptional factors.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PBX1 (9 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support Prevalence and architecture of de novo mutations in developmental disorders et al. (2017) No -
3 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
4 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
5 Recent Recommendation Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity Coe BP , et al. (2018) No -
6 Support - Pode-Shakked B et al. (2021) No -
7 Recent Recommendation - Zhou X et al. (2022) Yes -
8 Support - Marketa Wayhelova et al. (2024) Yes -
9 Support - Axel Schmidt et al. (2024) No -
Rare Variants   (16)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.*2820G>T - synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.701+1G>A - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.704G>A p.Arg235Gln missense_variant De novo - - 28135719 et al. (2017)
c.778T>C p.Tyr260His missense_variant De novo - - 28135719 et al. (2017)
c.679C>T p.Arg227Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.680G>A p.Arg227His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1236A>T p.Ser412%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.758A>C p.Tyr253Ser missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.1142C>T p.Thr381Ile missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.552dup p.Glu185ArgfsTer14 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.617G>C p.Arg206Pro missense_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.626G>C p.Ser209Thr missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.234del p.Phe78LeufsTer13 frameshift_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.320G>C p.Arg107Pro missense_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.649C>T p.Gln217Ter stop_gained Familial Maternal - 38321498 Marketa Wayhelova et al. (2024)
c.393_401del p.Ala133_Ala135del inframe_deletion De novo - Simplex 35982159 Zhou X et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo likely gene disruptive (LGD) variant and two de novo missense variants in the PBX1 gene were identified in ASD probands (De Rubeis et al., 2014; Yuen et al., 2017), while two additional de novo missense variants in this gene were identified in probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified PBX1 as a gene with an excess of missense variants (false discovery rata < 5%, count >1) (Coe et al., 2018).

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 de novo likely gene disruptive (LGD) variant and two de novo missense variants in the PBX1 gene were identified in ASD probands (De Rubeis et al., 2014; Yuen et al., 2017), while two additional de novo missense variants in this gene were identified in probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified PBX1 as a gene with an excess of missense variants (false discovery rata < 5%, count >1) (Coe et al., 2018).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A de novo likely gene disruptive (LGD) variant and two de novo missense variants in the PBX1 gene were identified in ASD probands (De Rubeis et al., 2014; Yuen et al., 2017), while two additional de novo missense variants in this gene were identified in probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified PBX1 as a gene with an excess of missense variants (false discovery rata < 5%, count >1) (Coe et al., 2018).

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

Increased from to 4

Description

A de novo likely gene disruptive (LGD) variant and two de novo missense variants in the PBX1 gene were identified in ASD probands (De Rubeis et al., 2014; Yuen et al., 2017), while two additional de novo missense variants in this gene were identified in probands with unspecified developmental disorders (Deciphering Developmental Disorders Study 2017). An integrated meta-analysis of de novo mutation data from a combined dataset of 10,927 individuals with neurodevelopmental disorders identified PBX1 as a gene with an excess of missense variants (false discovery rata < 5%, count >1) (Coe et al., 2018).

Krishnan Probability Score

Score 0.57113020567606

Ranking 823/25841 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 0.91058215118965

Ranking 3138/18225 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 0.45855558342655

Ranking 367/18665 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 0.3160186088615

Ranking 2504/20870 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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