Mosaic Variegated Aneuploidy Syndrome via the BUB1B Gene

Mosaic Variegated Aneuploidy (MVA) syndrome is a rare disease generally characterized by prenatal growth retardation, microcephaly, mental retardation, central nervous system abnormalities, and cancer predisposition (García-Castillo et al., 2008; Callier et al., 2005). Cancers can include Wilms tumor, rhabdomyosarcoma and leukemia (Hanks et al., 2004). MVA syndrome can be caused by mutations in the BUB1B gene. Individuals with monoallelic BUB1B mutations are often severely affected with Dandy-Walker complex, cataracts and Wilms Tumor, and exhibit cellular premature chromatid separation (latter also known as Premature Chromatid Separation (PCS) Trait/ Syndrome); whereas individuals with biallelic BUB1B mutations have a moderate phenotype (García-Castillo et al., 2008). Interestingly, an individual with gastric neoplasia and without the characteristic features of MVA syndrome was found to have an intronic homozygous intronic BUB1B mutation (Rio Frio et al., 2010). Lastly, individuals who have MVA syndrome and who do not have a germline pathogenic variant in BUB1B or premature chromatid separation are mildly affected and rarely get cancer (García-Castillo et al., 2008).

MVA syndrome is generally considered a rare autosomal recessive disorder that can be caused by pathogenic variants in the BUB1B gene; however individuals can also be affected with only one pathogenic mutation present. At the cellular level, >10% of cells exhibit mosaic aneuploidies. In addition, approximately 2/3 of metaphases from patients show PCS (García-Castillo et al., 2008). The BUB1B gene's product (BUBR1) is thought to be involved in the mitotic spindle checkpoint, which includes several proteins that sense microtubule attachment to kinetochores. BUB1B mutations can cause defects in the mitotic spindle checkpoint, spindle attachment or cause reduction of BUBR1 protein levels (Suijkerbuijk et al., 2010). There does not appear to be preferential specific chromosome gains and losses, and thus trisomies and monosomies appear to be random (Hanks and Rahman, 2005). Interestingly, while BUB1B mutations can occur in individuals who are predisposed to cancer (MVA syndrome), BUB1B mutations are rarely observed in somatic cancers (Hanks et al., 2006). Most pathogenic variants are missense or nonsense, but other mutations such as splice site changes, small insertions and duplications have also been reported (Human Gene Mutation Database). Missense mutations tend to occur in or near the BUBR1 kinase domain (Suijkerbuijk et al. 2010), and biallelic mutations appear to usually consist of one truncating and one missense variant (Hanks et al. 2006).

Analytical sensitivity should be high because the mutations reported are readily detectable by gene sequencing (Human Gene Mutation Database). Clinical sensitivity is unknown at this time since MVA syndrome is a rare disease and relatively few patients have been reported.

This test provides full coverage of all coding exons of the BUB1B gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).