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

Laura J. Grange, John J. Reynolds, Farid Ullah, Bertrand Isidor, Robert F. Shearer, Xenia Latypova, Ryan M. Baxley, Antony W. Oliver, Anil Ganesh, Sophie L. Cooke, Satpal S. Jhujh, Gavin S. McNee, Robert Hollingworth, Martin R. Higgs, Toyoaki Natsume, Tahir Khan, Gabriel Á. Martos-Moreno, Sharon Chupp, Christopher G. Mathew, David Parry, Michael A. Simpson, Nahid Nahavandi, Zafer Yüksel, Mojgan Drasdo, Anja Kron, Petra Vogt, Annemarie Jonasson, Saad Ahmed Seth, Claudia Gonzaga-Jauregui, Karlla W. Brigatti, Alexander P. A. Stegmann, Masato Kanemaki, Dragana Josifova, Yuri Uchiyama, Yukiko Oh, Akira Morimoto, Hitoshi Osaka, Zineb Ammous, Jesús Argente, Naomichi Matsumoto, Constance T.R.M. Stumpel, Alexander M. R. Taylor, Andrew P. Jackson, Anja-Katrin Bielinsky, Niels Mailand, Cedric Caignec (), Erica E. Davis () and Grant S. Stewart ()
Additional contact information
Laura J. Grange: University of Birmingham
John J. Reynolds: University of Birmingham
Farid Ullah: Ann & Robert H Lurie Children’s Hospital of Chicago
Bertrand Isidor: CHU Nantes
Robert F. Shearer: University of Copenhagen
Xenia Latypova: CHU Nantes
Ryan M. Baxley: University of Minnesota
Antony W. Oliver: University of Sussex, Falmer
Anil Ganesh: University of Birmingham
Sophie L. Cooke: University of Birmingham
Satpal S. Jhujh: University of Birmingham
Gavin S. McNee: University of Birmingham
Robert Hollingworth: University of Birmingham
Martin R. Higgs: University of Birmingham
Toyoaki Natsume: Research Organization of Information and Systems (ROIS)
Tahir Khan: Duke University Medical Center
Gabriel Á. Martos-Moreno: Universidad Autónoma de Madrid
Sharon Chupp: The Community Health Clinic
Christopher G. Mathew: University of the Witwatersrand
David Parry: The University of Edinburgh
Michael A. Simpson: King’s College London
Nahid Nahavandi: Human Genetics
Zafer Yüksel: Human Genetics
Mojgan Drasdo: Human Genetics
Anja Kron: Human Genetics
Petra Vogt: Human Genetics
Annemarie Jonasson: Human Genetics
Saad Ahmed Seth: King Fahad Military Medical Complex
Claudia Gonzaga-Jauregui: Regeneron Pharmaceuticals Inc.
Karlla W. Brigatti: Clinic for Special Children
Alexander P. A. Stegmann: Maastricht University Medical Center
Masato Kanemaki: The Graduate University for Advanced Studies (SOKENDAI)
Dragana Josifova: Guy’s Hospital
Yuri Uchiyama: Yokohama City University Hospital
Yukiko Oh: Jichi Medical University School of Medicine
Akira Morimoto: Jichi Medical University School of Medicine
Hitoshi Osaka: Jichi Medical University School of Medicine
Zineb Ammous: The Community Health Clinic
Jesús Argente: Universidad Autónoma de Madrid
Naomichi Matsumoto: Yokohama City University Hospital
Constance T.R.M. Stumpel: Maastricht University Medical Center
Alexander M. R. Taylor: University of Birmingham
Andrew P. Jackson: The University of Edinburgh
Anja-Katrin Bielinsky: University of Minnesota
Niels Mailand: University of Copenhagen
Cedric Caignec: Université de Toulouse
Erica E. Davis: Ann & Robert H Lurie Children’s Hospital of Chicago
Grant S. Stewart: University of Birmingham

Nature Communications, 2022, vol. 13, issue 1, 1-22

Abstract: Abstract 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-022-34349-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34349-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-34349-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().