Biallelic germline mutations in MAD1L1 induce a syndrome of aneuploidy with high tumor susceptibility.

Germline 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.This work is supported by Spanish Ministry of Science, Juan de la Cierva programme (C.V.-B.); Spanish Ministry of Science and Innovation, Agencia Estatal de Investigacion (MCI-AEI), BIO2017-91272-EXP (S.R.-P.); Spanish National Research and Development Plan, ISCIII, and FEDER, PI17/02303, PI20/01837, and DTS19/00111 (S.R.-P.); Spanish National Research and Development Plan, ISCIII, and FEDER, PI21/01641 (R.T.-R.); Fundacion Cientifica de la Asociacion Espanola contra el Cancer, LABAE20049RODR (S.R.-P.); MCI-AEI/FEDER, RTI2018-095582-B-I00, and RED2018-102723-T (M.M.); Comunidad de Madrid iLUNG and scCANCER programmes, B2017/BMD-3884 and Y2020/BIO-6519 (M.M.); and MCI-AEI, Severo Ochoa Center of Excellence, CEX2019-000891-S (S.R.-P., M.M., and M.U.).S