Based on well documented large-scale cytogenetic characterizations of hPSCs and parallel findings from cancer studies, we propose a model to explain recurrent karyotype changes found in hPSC (Fig. 3): disturbing the function of SAC components or mitosis machinery leads to defective cell division with missegregated whole or partially broken chromosomes and/or the formation of micronucleus with extensive DNA damage and fragmentation. The gene discussed is ADCY10; the disease is cancer.