Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy

Embryonic 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.

Citation

Grange, 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/s41467-022-34349-8

Type

Journal article

Language

en

Description

©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/s41467-022-34349-8

ISSN

2041-1723

EISSN

2041-1723

Sponsors

G.S.S., R.H., G.S.M., S.L.C., A.G. are funded by a CR-UK Program Grant (C17183/A23303). L.J.G. is supported by a joint funded University of Birmingham and CR-UK Ph.D studentship (C17422/A25154). J.J.R. and A.M.R.T. are supported by the University of Birmingham. S.S.J. is supported by a project grant funded by the Great Ormond Street Hospital Charity and Sparks (V5019). R.F.S. and N.Mai are supported by Novo Nordisk Foundation (NNF14CC0001) and Independent Research Fund Denmark (9040-00038B). D.P. and A.P.J. are supported by a European Union Horizon 2020 research and innovation program European Research Council (ERC) Advanced Grant (grant agreement 788093) and by a Medical Research Council (MRC) Unit core grant (U127580972). N.Mat is supported by AMED (JP21ek0109486, JP21ek0109549, and JP21ek0109493). Y.U. is supported by JSPS KAKENHI (JP21K15907). A.K.B. and R.M.B. are supported by grants from the National Institutes of Health (R01 GM134681 and R35 GM141805). F.U. is funded by the Higher Education Commission of Pakistan under the International research support initiative program (IRSIP). E.E.D. is supported by US National Institutes of Health grant R01 MH106826 and is the Ann Marie and Francis Klocke MD Research Scholar.

Collections

Faculty of Science and Engineering