Submission Details

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.