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

Author

Listed:
  • Laura J. Grange

    (University of Birmingham)

  • John J. Reynolds

    (University of Birmingham)

  • Farid Ullah

    (Ann & Robert H Lurie Children’s Hospital of Chicago
    Pakistan Institute of Engineering and Applied Sciences (PIEAS))

  • 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.
    Universidad Nacional Autónoma de México)

  • 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
    Yokohama City University Graduate School of Medicine)

  • 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
    IMDEA Alimentación/IMDEA Food)

  • 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
    Northwestern University)

  • Grant S. Stewart

    (University of Birmingham)

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.

Suggested Citation

  • 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., 2022. "Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34349-8
    DOI: 10.1038/s41467-022-34349-8
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    References listed on IDEAS

    as
    1. Sumedha Agashe & Chinnu Rose Joseph & Teresa Anne Clarisse Reyes & Demis Menolfi & Michele Giannattasio & Anja Waizenegger & Barnabas Szakal & Dana Branzei, 2021. "Smc5/6 functions with Sgs1-Top3-Rmi1 to complete chromosome replication at natural pause sites," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    2. Thomas Wechsler & Scott Newman & Stephen C. West, 2011. "Aberrant chromosome morphology in human cells defective for Holliday junction resolution," Nature, Nature, vol. 471(7340), pages 642-646, March.
    Full references (including those not matched with items on IDEAS)

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