Grange, Laura J.Reynolds, John J.Ullah, FaridIsidor, BertrandShearer, Robert F.Latypova, XeniaBaxley, Ryan M.Oliver, Antony W.Ganesh, AnilCooke, Sophie L.Jhujh, Satpal S.McNee, GavinHollingworth, RobertHiggs, Martin R.Natsume, ToyoakiKhan, TahirMartos-Moreno, Gabriel Á.Chupp, SharonMathew, Christopher G.Parry, DavidSimpson, Michael A.Nahavandi, NahidYüksel, ZaferDrasdo, MojganKron, AnjaVogt, PetraJonasson, AnnemarieSeth, Saad AhmedGonzaga-Jauregui, ClaudiaBrigatti, Karlla WStegmann, Alexander P.A.Kanemaki, MasatoJosifova, DraganaUchiyama, YuriOh, YukikoMorimoto, AkiraOsaka, HitoshiAmmous, ZinebArgente, JesúsMatsumoto, NaomichiStumpel, Constance T.R.M.Taylor, Alexander M.R.Jackson, Andrew P.Bielinsky, Anja-KatrinMailand, NielsLe Caignec, CedricDavis, Erica E.Stewart, Grant S.2025-04-032025-04-032022-11-04Grange, L.J., Reynolds, J.J., Ullah, F. et al. (2022) Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy. Nature Communications 13, 6664. https://doi.org/10.1038/s41467-022-34349-82041-172310.1038/s41467-022-34349-8https://wlv.openrepository.com/handle/2436/625891©2025 The Authors. Published by Springer Nature. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link: https://doi.org/10.1038/s41467-022-34349-8Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability.application/pdfenchromosomesDNA replicationgenomic instabilityneurodevelopmental disordersJournal article2041-1723Nature Communications6664