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

Author:

Grange Laura J.ORCID,Reynolds John J.ORCID,Ullah Farid,Isidor Bertrand,Shearer Robert F.ORCID,Latypova Xenia,Baxley Ryan M.ORCID,Oliver Antony W.ORCID,Ganesh Anil,Cooke Sophie L.ORCID,Jhujh Satpal S.ORCID,McNee Gavin S.,Hollingworth Robert,Higgs Martin R.ORCID,Natsume Toyoaki,Khan TahirORCID,Martos-Moreno Gabriel Á.,Chupp Sharon,Mathew Christopher G.ORCID,Parry DavidORCID,Simpson Michael A.ORCID,Nahavandi Nahid,Yüksel ZaferORCID,Drasdo Mojgan,Kron Anja,Vogt Petra,Jonasson Annemarie,Seth Saad AhmedORCID,Gonzaga-Jauregui Claudia,Brigatti Karlla W.,Stegmann Alexander P. A.ORCID,Kanemaki MasatoORCID,Josifova DraganaORCID,Uchiyama YuriORCID,Oh Yukiko,Morimoto Akira,Osaka HitoshiORCID,Ammous Zineb,Argente JesúsORCID,Matsumoto NaomichiORCID,Stumpel Constance T.R.M.,Taylor Alexander M. R.ORCID,Jackson Andrew P.,Bielinsky Anja-KatrinORCID,Mailand NielsORCID,Le Caignec CedricORCID,Davis Erica E.ORCID,Stewart Grant S.ORCID

Abstract

AbstractEmbryonic 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.

Funder

Cancer Research UK

Great Ormond Street Hospital Charity

Novo Nordisk UK Research Foundation

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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