s41467-022-34349-8.pdf (3.46 MB)
Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy
journal contribution
posted on 2023-06-10, 05:22 authored by Laura J Grange, John J Reynolds, Farid Ullah, Bertrand Isidor, Robert F Shearer, Xenia Latypova, Ryan M Baxley, Antony OliverAntony Oliver, Anil Ganesh, Sophie L Cooke, Satpal S Jhujh, Gavin S McNee, Robert Hollingworth, Martin R Higgs, othersEmbryonic 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.
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Publication status
- Published
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- Published version
Journal
Nature CommunicationsISSN
2041-1723Publisher
Springer Science and Business Media LLCExternal DOI
Volume
13Page range
a6664Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2022-11-10First Open Access (FOA) Date
2022-11-10First Compliant Deposit (FCD) Date
2022-11-10Usage metrics
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