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Mosaic Variegated Aneuploidy (MVA) syndrome is a rare, autosomal recessive disorder characterized by premature chromatid separation, growth retardation, microcephaly, hypotonia, developmental delay, and a high predisposition to childhood cancers. The condition is caused by biallelic mutations in the spindle assembly checkpoint gene BUB1B, encoding the mitotic checkpoint kinase BubR1, which ensures accurate chromosome segregation. Patients exhibit mosaic aneuploidies across multiple tissues and frequent tumor development including rhabdomyosarcoma, Wilms tumor, and leukemia (PMID:23916859).
Genetic evidence supports an autosomal recessive inheritance mode with biallelic BUB1B variants identified in multiple unrelated families. A monoallelic and a second undetected allele were reported in seven Japanese families with premature chromatid separation syndrome, later recognized as MVA (PMID:16411201). Two additional patients—a boy with infantile spasms and Dandy–Walker malformation carrying compound heterozygous variants c.498_505del and c.1288+5G>A (PMID:23916859) and an 11-year-old undergoing HSCT with c.498_505del (p.Asn167GlufsTer15) and c.1288+5G>A (PMID:31053147)—further confirm segregation in affected relatives (n = 7). A total of ≥8 probands have been reported with frameshift, splice‐site, and missense variants, including recurrent splice defect c.1402-5A>G (PMID:38102195).
The variant spectrum in MVA includes loss‐of‐function alleles (frameshift: c.498_505del (p.Asn167GlufsTer15); nonsense: c.2933G>A (p.Trp978Ter); splice: c.1402-5A>G) and missense mutations affecting kinase and kinetochore‐binding domains (e.g., c.2440C>G (p.Arg814Gly)) with no clear founder effect. Carrier frequency data are unavailable; however, compound heterozygosity and allelic heterogeneity underscore the critical requirement for intact BubR1 function in mitosis.
Functional studies demonstrate that patient‐derived cell lines harboring biallelic BUB1B mutations exhibit defective mitotic checkpoint activity, premature chromatid separation, and low BUBR1 protein abundance. Ectopic expression of wild-type BUB1B in these cells restores checkpoint function and chromosome alignment (PMID:20516114). Mouse models carrying the patient‐derived GTTA frameshift mutation recapitulate MVA features including aneuploidy, progeroid phenotypes, and cancer predisposition, confirming a loss‐of‐function mechanism (PMID:23300461).
No studies have convincingly refuted the BUB1B–MVA association, and no alternative molecular etiology has been identified in BUB1B‐negative MVA cases beyond CEP57 and TRIP13 defects. The concordance of genetic, cellular, and animal data establishes a robust genotype–phenotype correlation.
Collectively, biallelic loss‐of‐function mutations in BUB1B are definitively associated with mosaic variegated aneuploidy syndrome. Genetic testing for BUB1B variants informs diagnosis, prognosis, and familial counseling, while functional assays guide variant classification. Future therapeutic strategies may target mitotic checkpoint restoration.
Key take-home: BUB1B biallelic mutations cause autosomal recessive MVA syndrome by compromising BubR1‐mediated spindle checkpoint function, leading to early‐onset microcephaly, hypotonia, aneuploidy, and cancer risk.
Gene–Disease AssociationStrongBiallelic BUB1B mutations reported in ≥8 probands across seven families with segregation and consistent phenotypes Genetic EvidenceStrongMultiple unrelated AR cases (n=8) with frameshift, splice and missense variants and segregation in seven families Functional EvidenceModeratePatient cell lines and mouse models show impaired mitotic checkpoint, aneuploidy and rescue by wild-type BUB1B expression |