Villarroya-Beltri, CarolinaOsorio, AnaTorres-Ruiz, RaúlGómez-Sánchez, DavidTrakala, MariannaSánchez-Belmonte, AgustinMercadillo, FátimaHurtado, BegoñaPitarch, BorjaHernández-Núñez, AlmudenaGómez-Caturla, AntonioRueda, DanielPerea, JoséRodriguez Perales, SandraMalumbres, MarcosUrioste, Miguel2024-03-152024-03-152022-11-04Sci Adv . 2022 ;8(44):eabq591http://hdl.handle.net/20.500.12105/18962Germline mutations leading to aneuploidy are rare, and their tumor-promoting properties are mostly unknown at the molecular level. We report here novel germline biallelic mutations in MAD1L1, encoding the spindle assembly checkpoint (SAC) protein MAD1, in a 36-year-old female with a dozen of neoplasias. Functional studies demonstrated lack of full-length protein and deficient SAC response, resulting in ~30 to 40% of aneuploid blood cells. Single-cell RNA analysis identified mitochondrial stress accompanied by systemic inflammation with enhanced interferon and NFκB signaling both in aneuploid and euploid cells, suggesting a non-cell autonomous response. MAD1L1 mutations resulted in specific clonal expansions of γδ T cells with chromosome 18 gains and enhanced cytotoxic profile as well as intermediate B cells with chromosome 12 gains and transcriptomic signatures characteristic of leukemia cells. These data point to MAD1L1 mutations as the cause of a new variant of mosaic variegated aneuploidy with systemic inflammation and unprecedented tumor susceptibility.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/Attribution-NonCommercial-NoDerivatives 4.0 Internacional36322655844eabq591410.1126/sciadv.abq59142375-2548Science advancesopen access