BUB1B – Mosaic variegated aneuploidy syndrome 1

BUB1B (HGNC:1149) encodes the mitotic checkpoint kinase BubR1, essential for accurate chromosome segregation during cell division. Germline variants in BUB1B cause mosaic variegated aneuploidy syndrome 1, an autosomal recessive disorder marked by early‐onset diffuse mosaic aneuploidies, growth retardation, microcephaly, and cancer predisposition.

Autosomal recessive inheritance is supported by compound heterozygous or homozygous BUB1B variants in at least seven unrelated probands from five families, with unaffected heterozygous parents and affected offspring (PMID:16411201; PMID:38664248; PMID:38102195). A representative truncating allele is c.580C>T (p.Arg194Ter) (PMID:38664248), demonstrating loss of function.

The variant spectrum includes nonsense (e.g., p.Arg194Ter), frameshift (c.1833del, p.Phe611fs), splice‐site (c.1402-5A>G), intronic transposon insertion, and missense substitutions clustering in the kinase domain. All classes result in marked reduction of BubR1 abundance or kinase activity, abolishing the spindle assembly checkpoint.

Functional assays in patient‐derived cells show impaired kinetochore localization of BubR1, defective spindle checkpoint activity, and elevated chromosomal instability, which is rescued by ectopic wild‐type BUB1B expression (PMID:20516114). RNA sequencing with long‐read mapping identified a 3 kb Alu/SVA insertion in intron 2 causing aberrant splicing and almost complete loss of BubR1 protein (PMID:38102195). Haploinsufficient Bub1b mouse models recapitulate aneuploidy phenotypes, confirming a loss‐of‐function mechanism.

No studies have refuted the causal link between biallelic BUB1B mutations and MVA1. While isolated cases present with sudden postnatal collapse and hypoxic‐ischemic encephalopathy features, the core phenotype of mosaic aneuploidy and cancer risk remains consistent across reports (PMID:38664248).

In summary, definitive clinical and experimental evidence establishes that biallelic loss‐of‐function variants in BUB1B cause mosaic variegated aneuploidy syndrome 1. Molecular diagnosis enables accurate genetic counseling, carrier detection, and proactive surveillance for malignancy in affected families.

References

• American journal of medical genetics. Part A • 2006 • Monoallelic BUB1B mutations and defective mitotic-spindle checkpoint in seven families with premature chromatid separation syndrome PMID:16411201
• Cancer research • 2010 • Molecular causes for BUBR1 dysfunction in the human cancer predisposition syndrome mosaic variegated aneuploidy. PMID:20516114
• Journal of human genetics • 2024 • RNA sequencing and target long-read sequencing reveal an intronic transposon insertion causing aberrant splicing. PMID:38102195
• International journal of legal medicine • 2024 • Sudden unexpected postnatal collapse and BUB1B mutation: first forensic case report. PMID:38664248

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