TOP2B

protein-coding

DNA topoisomerase II beta, the group of Topoisomerases

Gene summary

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. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]

MANE transcript

NM_001330700.2

Inheritance

ClinVar variants

P:7U:542B:270

Top phenotype

B-cell immunodeficiency, distal limb anomalies, and urogenital malformations

gnomAD constraint

pLI —, LoF o/e 0.15

Max pathogenic AF

—

Genomic locus

chr3:25,597,978-25,664,909

External References & Databases

Ensembl (ENSG00000077097)

Transcript & Mutation Effects

hg38 • Region Span ~66.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

B-cell immunodeficiency, distal limb anomalies, and urogenital malformationsMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0012243

Submitter: ClinGen

TOP2B was first reported in relation to autosomal dominant B-cell immunodeficiency, distal limb anomalies, and urogenital malformations in 2019 (Broderick L, et al., 2019, PMID: 31409799). Dominant negative mutations in the TOP2B gene, encoding DNA topoisomerase 2-beta, cause Hoffman syndrome (also known as BILU syndrome) with humoral b-cell immunodeficiency, distal limb anomalies, dysmorphic facial features, and urogenital malformations. Three missense variants and one in-frame deletion in the TOPRIM domain have been reported in six probands, and three additional family members, in three publications (PMIDs: 31409799, 32128574, and 33459963). This gene-disease association is supported by its function, generating transient double-stranded DNA breaks that alleviate negative supercoils (PMID: 10684600). Failure to relax topological stress in patient cells (PMID: 32128574) can reduce the production of multiple gene products, and cause loss of function of large genes, which are most vulnerable to topologic stress. Many B-cell-specific transcription factor genes are relatively long and require TOP2B for efficient transcription, suggesting a pathogenesis mechanism for the TOP2B mutations and the role of TOP2B in B-cell development (PMID: 31409799). Additionally, there are b-cell specific knockout and knock-in mouse models that recapitulates disease (PMID: 31409799). In summary, there is moderate evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.

neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: Ambry Genetics

B-cell immunodeficiency, distal limb anomalies, and urogenital malformationsMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0012243

Submitter: Illumina

B-cell immunodeficiency, distal limb anomalies, and urogenital malformationsSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012243

Submitter: PanelApp Australia

B-cell immunodeficiency, distal limb anomalies, and urogenital malformationsMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0012243

Submitter: Ambry Genetics

B-cell immunodeficiency, distal limb anomalies, and urogenital malformationsSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012243

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

B-cell immunodeficiency, distal limb anomalies, and urogenital malformationsAD

Manifestation: Allergy/Immunology/Infectious; Craniofacial; Genitourinary; Musculoskeletal

Intervention: Allergy/Immunology/Infectious

Rationale: Among other features, the condition can involve susceptibilty to infections, and awareness may allow preventative measures and early and aggressive treatment of infections

Refs: 31409799; 32128574; 33459963

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TOP2B variants in ClinVar

11 Conditions Cataloged

not providedTotal: 1078

not specifiedTotal: 224

TOP2B-related disorderTotal: 32

B-cell immunodeficiency, distal limb anomalies, and urogenital malformationsTotal: 19

See casesTotal: 2

Neurodevelopmental disorderTotal: 1

Primary ciliary dyskinesiaTotal: 1

TOP2B-related neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001330700.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			7 clinvar	231 clinvar	10 clinvar	248
missense	2 clinvar	4 clinvar	496 clinvar	26 clinvar	1 clinvar	529
nonsense		1 clinvar	10 clinvar			11
start loss			1 clinvar			1
frameshift			15 clinvar		1 clinvar	16
splice donor/acceptor (+/-2bp)			13 clinvar	1 clinvar		14
Total	2	5	542	258	12	819

Highest pathogenic variant AF is 0.00004984122

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 40 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001330700.2	RefSeq	NP_001317629.1	36	MANE Select
ENST00000264331.9	Ensembl	ENSP00000264331.4	36	MANE Select
NM_001068.3	RefSeq	NP_001059.2	36	Standard
ENST00000413971.5	Ensembl	ENSP00000388216.1	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
top2b	Danio rerio	Structure: retinal bipolar neuron Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

top2b

Danio rerio

Structure: retinal bipolar neuron

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Doxorubicin Pathway (Cardiomyocyte Cell), Pharmacodynamics
Etoposide Pathway, Pharmacokinetics/Pharmacodynamics
Etoposide Action Pathway
Etoposide Metabolism Pathway
Post-translational protein modification

Biological Process

resolution of meiotic recombination intermediates
sister chromatid segregation
neuron migration
DNA topological change
axonogenesis

Molecular Function

DNA binding
chromatin binding
DNA topoisomerase type II (ATP-hydrolyzing) activity
protein kinase C binding
ATP binding

Cellular Component

heterochromatin
nucleus
nucleoplasm
nucleolus
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000435706
Coding exons: 36
Length: 66924
Individuals with no LoFs: 124626
Homozygous LoFs: 0
Heterozygous LoFs: 26
Defined: 124652
p: 0.000104

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.86	474	777	0.610	0.0000383	10705
Missense (PolyPhen)		53	212.73	0.24914		2820
Synonymous	0.865	245	263	0.932	0.0000130	2891
Loss of Function	6.97	12	78.8	0.152	0.00000401	1131

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000065	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00057	0.00050	rare
Finnish	0.00019	0.00019	rare
European (Non-Finnish)	0.000063	0.000062	rare
South Asian	0.00013	0.00013	rare
Other	0.00017	0.00017	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks. {ECO:0000269|PubMed:10684600}.;
Disease: DISEASE: Note=A defect in TOP2B is associated with autism spectrum disorder (ASD). {ECO:0000269|PubMed:28343847}.;

Recessive Scores

pRec: 0.375

Intolerance Scores

LoFtool: 0.820
RVIS EVS: -0.15
RVIS percentile EVS: 42.28

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.878

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium