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TOP2B encodes type II topoisomerase beta, which controls topological changes during DNA transcription and is critically expressed in the developing nervous system. Functional studies demonstrate its role in neuronal differentiation and survival ([PMID:24463367]). Recent reports describe recurrent de novo missense alterations linking TOP2B to Neurodevelopmental disorder.
Trio-based exome sequencing identified a de novo missense TOP2B variant, c.187C>T (p.His63Tyr), in a 7-year-old girl with muscle hypotonia, stereotypic hand movements, epilepsy, global developmental delay and autism spectrum disorder. This variant was previously reported in another unrelated individual, supporting pathogenicity in two probands ([PMID:31953910]). Both cases lack familial segregation beyond de novo status.
Inheritance follows an autosomal dominant pattern with recurrent de novo occurrence. To date, only missense variants affecting conserved residues have been documented; no truncating, splice, or structural variants have been reported. Population frequency and carrier rate data are not yet available.
In vivo studies in Top2b-deficient mice reveal delayed neuronal differentiation, degeneration of retinal plexiform layers, and reduced survival of postmitotic neurons, paralleling human neurodevelopmental deficits ([PMID:24463367]). These findings support a haploinsufficiency mechanism rather than dominant-negative effects.
No conflicting clinical data or benign recurrent variants have been reported to dispute this association. However, further case series and variant-specific functional assays are needed to strengthen genotype–phenotype correlations.
In summary, combined genetic and experimental evidence achieve a moderate level of support for a causative role of TOP2B missense variants in neurodevelopmental disorder. Inclusion of TOP2B in diagnostic gene panels for neurodevelopmental disorders is recommended, and further mechanistic studies are warranted.
Gene–Disease AssociationModerateTwo unrelated de novo cases with identical p.His63Tyr variants and supportive murine functional data Genetic EvidenceModerateTwo de novo missense p.His63Tyr variants in unrelated individuals ([PMID:31953910]) Functional EvidenceLimitedTop2b-deficient mice exhibit neuronal differentiation delay and neuron survival deficits overlapping human phenotype ([PMID:24463367]) |