Using exome sequencing and a variant prioritization strategy that focuses on loss-of-function variants, we identified biallelic, loss-of-function CEP57 mutations as a cause of constitutional mosaic aneuploidies. CEP57 is a centrosomal protein and is involved in nucleating and stabilizing microtubules. Our findings indicate that these and/or additional functions of CEP57 are crucial for maintaining correct chromosomal number during cell division.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


NCBI Reference Sequence


  1. 1.

    et al. Nat. Rev. Mol. Cell Biol. 10, 478–487 (2009).

  2. 2.

    et al. Genetics 179, 737–746 (2008).

  3. 3.

    et al. Am. J. Med. Genet. A. 146A, 1687–1695 (2008).

  4. 4.

    et al. Nat. Genet. 36, 1159–1161 (2004).

  5. 5.

    et al. Nature 426, 570–574 (2003).

  6. 6.

    et al. Biochem. J. 412, 265–273 (2008).

  7. 7.

    et al. Am. J. Med. Genet. 110, 273–277 (2002).

  8. 8.

    et al. Traffic 10, 1765–1772 (2009).

  9. 9.

    et al. Nat. Rev. Mol. Cell Biol. 8, 379–393 (2007).

  10. 10.

    et al. Cancer Res. 70, 4891–4900 (2010).

  11. 11.

    et al. Nucleic Acids Res. 38, D652–D657 (2010).

  12. 12.

    et al. Hum. Mol. Genet. 19, R119–R124 (2010).

  13. 13.

    et al. Nat. Genet. 42, 790–793 (2010).

Download references


We are very grateful to all the families that participated in this study and to A. Zachariou, M. Warren-Perry, R. Linger, D. Dudakia and J. Bull for assistance in their recruitment. We thank D. Leongamornlert for assistance with exome sequencing, A. Renwick, S. Seal, G. Bowden, D. Hughes and C. Turnbull for assistance in Solexa optimization and validation experiments and B. Ebbs for DNA extraction and for running the ABI sequencer. We thank K. Tatton-Brown for assistance with clinical review of cases, A.I. Vasquez and J. Swansbury for the karyotyping and A. Strydom for secretarial assistance with the manuscript. K.S. is supported by the Michael and Betty Kadoorie Cancer Genetics Research Programme. We acknowledge NHS funding to the National Institute for Health Research Biomedical Research Centre. This work was supported by Cancer Research UK (grants C8620_A9024 and C8620_A8857) and the Institute of Cancer Research (UK).

Author information

Author notes

    • Katie Snape
    •  & Sandra Hanks

    These authors contributed equally to this work.


  1. Section of Cancer Genetics, Institute of Cancer Research, Sutton, UK.

    • Katie Snape
    • , Sandra Hanks
    • , Elise Ruark
    • , Anna Elliott
    • , Anne Murray
    • , Jenny Douglas
    •  & Nazneen Rahman
  2. División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco, México.

    • Patricio Barros-Núñez
  3. Division of Pediatric Endocrinology, State University of New York at Stony Brook, Stony Brook, New York, USA.

    • Andrew H Lane
  4. Clinical Genetics Service, City Hospital, Nottingham, UK.

    • Nora Shannon
  5. Service de Cytogénétique, Centre Hospitalier Universitaire (CHU) de Dijon, Dijon, France.

    • Patrick Callier
  6. The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital and Division of Clinical & Metabolic Genetics, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.

    • David Chitayat
  7. Manchester Biomedical Research Center, Manchester Academic Health Sciences Center, St. Mary's Hospital, Manchester, UK.

    • Jill Clayton-Smith
  8. Medical Research Council (MRC) Human Genetics Unit, Institute of Genetic and Molecular Medicine, Western General Hospital, Edinburgh, UK.

    • David R FitzPatrick
  9. Department of Clinical Genetics, Lund University, University and Regional Laboratories, Skåne University Hospital, Lund, Sweden.

    • David Gisselsson
  10. Division of Medical Genetics, CHU Vaudois, Lausanne, Switzerland.

    • Sebastien Jacquemont
  11. Ninewells Hospital and Medical School, Tayside University Hospitals National Health Service (NHS) Trust, Dundee, UK.

    • Keiko Asakura-Hay
  12. Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak & Oakland University William Beaumont School of Medicine, Rochester, Michigan, USA.

    • Mark A Micale
  13. Department of Clinical Genetics, Ferguson-Smith Centre, Royal Hospital for Sick Children, Glasgow, UK.

    • John Tolmie
  14. Peninsula Clinical Genetics Service and Peninsula Medical School, Royal Devon & Exeter Healthcare NHS Trust, Exeter, UK.

    • Peter D Turnpenny
  15. Northern Genetics Service, Newcastle upon Tyne Hospitals Foundation Trust, Newcastle upon Tyne, UK.

    • Michael Wright


  1. Search for Katie Snape in:

  2. Search for Sandra Hanks in:

  3. Search for Elise Ruark in:

  4. Search for Patricio Barros-Núñez in:

  5. Search for Anna Elliott in:

  6. Search for Anne Murray in:

  7. Search for Andrew H Lane in:

  8. Search for Nora Shannon in:

  9. Search for Patrick Callier in:

  10. Search for David Chitayat in:

  11. Search for Jill Clayton-Smith in:

  12. Search for David R FitzPatrick in:

  13. Search for David Gisselsson in:

  14. Search for Sebastien Jacquemont in:

  15. Search for Keiko Asakura-Hay in:

  16. Search for Mark A Micale in:

  17. Search for John Tolmie in:

  18. Search for Peter D Turnpenny in:

  19. Search for Michael Wright in:

  20. Search for Jenny Douglas in:

  21. Search for Nazneen Rahman in:


S.H., J.D. and A.M. performed exome sequencing. K.S., E.R., A.E. and N.R. performed data management and analysis. S.H. and J.D. performed CEP57 mutation and dosage analysis. P.B.-N., A.H.L., N.S., P.C., D.C., J.C.-S., D.R.F., D.G., S.J., K.A.-H., M.A.M., J.T., P.D.T. and M.W. provided clinical material. N.R. wrote the manuscript with substantial input from K.S., S.H., E.R. and J.D. N.R. designed and oversaw all aspects of the study.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Nazneen Rahman.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Methods, Supplementary Tables 1–5 and Supplementary Figures 1–4.

About this article

Publication history






Further reading