This variant is classified as a variant of unknown significance because its contribution to mosaic variegated aneuploidy syndrome (see MVA1, 257300) has not been confirmed.
In a 54-year-old 46,XY Japanese woman with instability of chromosome numbers (mosaic variegated aneuploidy syndrome, MVA) and spindle assembly checkpoint failure, who was negative for mutation in known MVA-associated genes, Fujita et al. (2020) performed exome sequencing and identified heterozygosity for a de novo c.856C-A transversion (c.856C-A, NM_001255.3) in the CDC20 gene, resulting in an arg286-to-ser (R286S) substitution at a highly conserved residue within the third WD40 repeat, at the binding site for BUBR1 (BUB1B; 602860). Analysis of patient cells revealed evidence of mosaic variegated aneuploidy syndrome (MVA), with random gain and loss of various chromosomes in 15% of cells, without detectable chromosome breakage. Premature chromatid separation was observed in about 6% of cells, and micronuclei were present in 2.5% of cells, indicating chromosome missegregation. Treatment of patient cells with a microtubule depolymerizing reagent resulted in accumulation of octoploid cells, consistent with aberrant cell cycle exit from metaphase due to spindle assembly checkpoint failure. Mutant CDC20 showed lower binding affinity to BUBR1 during the formation of the mitotic checkpoint complex (MCC), but not during the interaction between MCC and the anaphase-promoting complex (APC; see 608473)/cyclosome-CDC20 complex. The authors noted that whereas heterozygous knockout of CDC20 did not induce spindle assembly checkpoint (SAC) failure, knockin of the mutant CDC20 induced SAC failure and random aneuploidy in cultured cells, indicating that the pathogenicity of the R286S variant likely results from imbalance between the MCC and APC/C-CDC20 complexes. The authors suggested that accelerated chromosome number instability may induce premature aging in humans, possibly associated with early loss of stem cells. The proband exhibited short stature and a progeroid appearance with loss of body and scalp hair, dry atrophic skin with hyper- and hypopigmented macules, and bilateral cataracts, as well as bilateral renal failure, necrosis of the femoral head, bone marrow hypoplasia with severe anemia, and hypothyroidism. She also had streak gonads, low cardiac output, kyphosis, leg-length discrepancy, atrophy of oral mucosa, and nail deformities. Exome sequencing also revealed homozygosity for a splice site mutation in the CENPT gene (611510), predicted to result in an in-frame deletion. Mutant CENPT correctly localized to the kinetochore in patient cells, and further studies involving CENPT were not performed. The authors stated that more patients would be required to determine whether the phenotype was induced by a combination of the CDC20 and CENPT mutations, or by the CDC20 mutation alone.
