Human Gene Module / Chromosome 3 / TOP2B

TOP2BDNA topoisomerase II beta

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 8
Rare Variants / Common Variants
7 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
3p24.2
Associated Disorders
-
Relevance to Autism

TOP2B was identified as an ASD candidate gene based on having a p-value < 0.001 following DeNovoWEST analysis of de novo variants in 16,877 ASD trios from the Simons Simplex Collection, the Autism Sequencing Consortium, the MSSNG cohort, and the SPARK cohort in Zhou et al., 2022; among the de novo variants observed in ASD cases in this analysis were three damaging de novo missense variants (defined as having a REVEL score > 0.5). The same de novo missense variant in TOP2B (c.187C>T;p.His63Tyr) was previously reported in two unrelated individuals presenting with developmental delay, intellectual disability, hypotonia, and autism spectrum disorder or autistic features, among other phenotypes (Lam et al., 2017; Hiraide et al., 2020). Knockdown of Top2b in neurons resulted in reduced expression of long (>200 kilobases) genes; many high-confidence ASD candidate genes are exceptionally long (King et al., 2013).

Molecular Function

This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This nuclear enzyme is involved in processes such as chromosome condensation, chromatid separation, and the relief of torsional stress that occurs during DNA transcription and replication. It catalyzes the transient breaking and rejoining of two strands of duplex DNA which allows the strands to pass through one another, thus altering the topology of DNA. Two forms of this enzyme exist as likely products of a gene duplication event. The gene encoding this form, beta, is localized to chromosome 3 and the alpha form is localized to chromosome 17. The gene encoding this enzyme functions as the target for several anticancer agents and a variety of mutations in this gene have been associated with the development of drug resistance. Reduced activity of this enzyme may also play a role in ataxia-telangiectasia.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
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Reports related to TOP2B (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Topoisomerases facilitate transcription of long genes linked to autism King IF , et al. (2013) No -
2 Support - Lam CW et al. (2017) No Autistic features
3 Support - Hiraide T et al. (2020) Yes -
4 Primary - Zhou X et al. (2022) Yes -
5 Support - Morotomi-Yano K et al. (2022) Yes -
6 Support - Sheth F et al. (2023) Yes DD, ID
7 Support - Sabin A Nettles et al. (2023) No -
8 Support - Ashlesha Gogate et al. (2024) Yes -
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.187C>T p.His63Tyr missense_variant De novo - - 28343847 Lam CW et al. (2017)
c.1406G>A p.Gly469Asp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1469C>T p.Ala490Val missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.187C>T p.His63Tyr missense_variant De novo - Simplex 31953910 Hiraide T et al. (2020)
c.1507G>A p.Gly503Arg missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.3925G>C p.Glu1309Gln missense_variant Familial Paternal Simplex 37543562 Sheth F et al. (2023)
c.41G>C p.Gly14Ala missense_variant Familial Both parents Multiplex 39632905 Ashlesha Gogate et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

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.

10/1/2022
icon
2

Increased from to 2

Krishnan Probability Score

Score 0.60171844834031

Ranking 389/25841 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 0.99731109311551

Ranking 1329/18225 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 0.94245594044339

Ranking 15313/18665 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 0.43142519217842

Ranking 1102/20870 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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