Genotypes and Phenotypes of a Novel Neurodevelopmental Disorder Caused by Biallelic Mutations in BUB1

Background/Purpose: Budding uninhibited by benzimidazoles (BUB1) contributes to multiple mitotic processes. We described the first two patients with biallelic BUB1 germline mutations, who both display microcephaly, intellectual disability, and several patient-specific features.

Methods: Short-read exome sequencing, RNAseq, large-scale standard karyotyping, live cell imaging, quantitative imaging analysis, cohesion defect analysis, immunofluorescence, immunoblotting, clinical phenotyping

Results: The identified mutations cause reduced total protein level and kinase activity, leading to distinct mitotic defects. Both patients’ cells show prolonged mitosis duration, chromosome segregation errors, and an overall functional spindle assembly checkpoint. However, while BUB1 levels mostly affect BUBR1 kinetochore recruitment, impaired kinase activity prohibits centromeric recruitment of Aurora B, SGO1, and TOP2A, correlating with anaphase bridges, aneuploidy, and defective sister chromatid cohesion. At a very low level, railroad chromosomes and variegated mosaic aneuploidy could be observed in fibroblasts of both patients. Both patients showed decreased pH2A-T120 levels; however, at varying degrees. We hypothesize that unresolved DNA catenanes increase cohesion strength, with concomitant increase in anaphase bridges.

Conclusion: In conclusion, we showed that BUB1 mutations cause a neurodevelopmental disorder, with clinical and cellular phenotypes that partially resemble previously described syndromes, including autosomal recessive primary microcephaly, mosaic variegated aneuploidy, and cohesinopathies (Carvalhal et al., 2022). We discuss the question of cancer susceptibility, and we are looking for further patients with BUB1-related neurodevelopmental disorders. Please contact: [e-mail].