733 Identification and molecular characterization of a CDC20 mutation in a novel mosaic variegated aneuploidy syndrome with premature aging phenotypes

The spindle assembly checkpoint (SAC) ensures proper chromosome segregation during mitosis. When defective, it causes mosaic variegated aneuploidy (MVA), a chromosome anomaly characterized by mosaic random multiple aneuploidies. Defects in SAC can cause premature aging, which has been suspected in mouse studies, but remains elusive in humans. Here, we identified a 48-year-old proband with MVA and premature aging phenotypes. The proband showed developmental delay without mental retardation in childhood. Premature aging phenotypes appeared from her 20s to 40s, including poikiloderma, subcutaneous fat loss, total hair loss, cataracts, renal failure, and total anemia with bone marrow hypoplasia. G-band karyotyping showed MVA in ∼15% of her peripheral blood leukocytes. She did not have microcephaly or the childhood cancers that typically appear in known MVA syndromes. Whole-exome sequencing identified a missense mutation of the SAC gene CDC20 in the proband, but not in her parents, while no disease-causative mutations were found in the genes of premature aging or MVA syndromes. An immunoprecipitation assay revealed that the mutation significantly reduced the binding affinity of CDC20 to the N-terminus of BUBR1, an important regulator of SAC. The HCT116 cells in which the proband mutation was introduced via CRISPR/Cas9 showed SAC deficiency similar to the peripheral blood leukocytes of the proband. These results indicate that the mutation is pathogenic. Our findings indicate that CDC20 is a novel causative gene of MVA syndrome and suggest that SAC defects could cause premature aging in humans.