Human Gene Module / Chromosome 2 / OTX1

OTX1orthodenticle homeobox 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
2 / 4
Rare Variants / Common Variants
1 / 2
Aliases
-
Associated Syndromes
-
Chromosome Band
2p15
Associated Disorders
-
Relevance to Autism

In OTX1, rs2018650 and rs13000344 were associated with autism in ASD-CARC cohorts (P(FDR)=8.65 x 10(-7) and 6.07 x 10(5), respectively), AGRE cohort (P(FDR)=0.0034 and 0.015, respectively) and the combined families (P(FDR)=2.34 x 10(-9) and 0.00017, respectively); associations were marginal or insignificant in the New York and SIRFA cohorts. These results indicate that deletion 2p15-p16.1 is not commonly associated with idiopathic ASD, but represents a novel contiguous gene syndrome associated with a constellation of phenotypic features (autism, intellectual disability, craniofacial/CNS dysmorphology), and that OXT1 may contribute to ASD in 2p15-p16.1 deletion cases and non-deletion cases of ASD mapping to this chromosome region.

Molecular Function

This gene encodes a member of the bicoid sub-family of homeodomain-containing transcription factors. The encoded protein acts as a transcription factor and may play a role in brain and sensory organ development. A similar protein in mouse is required for proper brain and sensory organ development and can cause epilepsy.

External Links
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SFARI Genomic Platforms
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Reports related to OTX1 (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary 2p15-p16.1 microdeletion syndrome: molecular characterization and association of the OTX1 and XPO1 genes with autism spectrum disorders Liu X , et al. (2011) Yes -
2 Recent recommendation - Taehwan Shin et al. (2024) Yes -
3 Highly Cited Otx1 and Otx2 define layers and regions in developing cerebral cortex and cerebellum Frantz GD , et al. (1994) No -
4 Highly Cited Epilepsy and brain abnormalities in mice lacking the Otx1 gene Acampora D , et al. (1996) No -
Rare Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
C>A - 2KB_upstream_variant Familial Both parents Unknown 39019033 Taehwan Shin et al. (2024)
Common Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- - intergenic_variant - - - 21750575 Liu X , et al. (2011)
c.*89T>C - intergenic_variant - - - 21750575 Liu X , et al. (2011)
SFARI Gene score
2

Strong Candidate

Two SNPs in the OTX1 gene were associated with autism in ASD-CARC cohorts (P(FDR)=8.65 x 10(-7) and 6.07 x 10(5), respectively), AGRE cohort (P(FDR)=0.0034 and 0.015, respectively) and the combined families (P(FDR)=2.34 x 10(-9) and 0.00017, respectively); associations were marginal or insignificant in the New York and SIRFA cohorts (PMID 21750575). Mice lacking the Otx1 gene display spontaneous epileptic behaviour and multiple brain abnormalities (PMID 8841200).

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

Two SNPs in the OTX1 gene were associated with autism in ASD-CARC cohorts (P(FDR)=8.65 x 10(-7) and 6.07 x 10(5), respectively), AGRE cohort (P(FDR)=0.0034 and 0.015, respectively) and the combined families (P(FDR)=2.34 x 10(-9) and 0.00017, respectively); associations were marginal or insignificant in the New York and SIRFA cohorts (PMID 21750575). Mice lacking the Otx1 gene display spontaneous epileptic behaviour and multiple brain abnormalities (PMID 8841200).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Two SNPs in the OTX1 gene were associated with autism in ASD-CARC cohorts (P(FDR)=8.65 x 10(-7) and 6.07 x 10(5), respectively), AGRE cohort (P(FDR)=0.0034 and 0.015, respectively) and the combined families (P(FDR)=2.34 x 10(-9) and 0.00017, respectively); associations were marginal or insignificant in the New York and SIRFA cohorts (PMID 21750575). Mice lacking the Otx1 gene display spontaneous epileptic behaviour and multiple brain abnormalities (PMID 8841200).

Reports Added
[New Scoring Scheme]
7/1/2015
icon
4

Increased from to 4

Description

Two SNPs in the OTX1 gene were associated with autism in ASD-CARC cohorts (P(FDR)=8.65 x 10(-7) and 6.07 x 10(5), respectively), AGRE cohort (P(FDR)=0.0034 and 0.015, respectively) and the combined families (P(FDR)=2.34 x 10(-9) and 0.00017, respectively); associations were marginal or insignificant in the New York and SIRFA cohorts (PMID 21750575). Mice lacking the Otx1 gene display spontaneous epileptic behaviour and multiple brain abnormalities (PMID 8841200).

Krishnan Probability Score

Score 0.49349245445382

Ranking 4110/25841 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 0.21980790353516

Ranking 6923/18225 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 0.86435670335976

Ranking 4037/18665 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 15

Ranking 131/461 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 -0.046157638073634

Ranking 10280/20870 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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