Recurrent Neurodevelopmental Disorder Associated With a Dominant‐Negative TOP2B H63Y Variant

We describe a 7 year-old boy with severe neurodevelopmental disorder, medically-refractory epileptic encephalopathy, hyperkinetic movement disorder, hypotonia, cerebral and cerebellar atrophy and hypomyelination who was found to have a heterozygous de novo TOP2B NM_001330700.2:c.187C>T, p.(His63Tyr) variant. This is the third individual reported with the H63Y variant and severe neurodevelopmental disorder. The phenotype associated with the H63Y variant differs greatly from the TOP2B-related Immunodeficiency and Congenital Anomalies Spectrum (TICAS) syndrome that has been reported with heterozygous loss-of-function variants affecting the TOPRIM domain and adjacent regions of TOP2B. DNA topoisomerase II beta (TOP2B) is an essential enzyme that resolves DNA supercoils and knots to facilitate transcription and replication. To investigate the functional impact of this variant, we studied the homologous yeast variant, top2 H20Y (H20Y). Homozygous H20Y strains exhibited reduced viability, while heterozygous H20Y acted as a loss-of-function allele incapable of supporting growth. Overexpression of the chimeric human H63Y variant in yeast was lethal. Despite its dysfunction, H63Y retains partial enzymatic activity and appears to function as a dominant negative variant that induces DNA damage. Thus, this work establishes a novel gene-disease association between TOP2B-H63Y and a neurodevelopmental disorder we propose to name TOP2B-related neurodevelopmental disorder. Further studies should elucidate the pathogenic mechanisms underlying H63Y-associated phenotypes.