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Diagnostic value of exome and whole genome sequencing in craniosynostosis
  1. Kerry A Miller1,
  2. Stephen R F Twigg1,
  3. Simon J McGowan2,
  4. Julie M Phipps1,3,
  5. Aimée L Fenwick1,
  6. David Johnson4,
  7. Steven A Wall4,
  8. Peter Noons5,
  9. Katie E M Rees6,
  10. Elizabeth A Tidey6,
  11. Judith Craft7,
  12. John Taylor7,
  13. Jenny C Taylor8,9,
  14. Jacqueline A C Goos10,
  15. Sigrid M A Swagemakers11,
  16. Irene M J Mathijssen10,
  17. Peter J van der Spek11,
  18. Helen Lord7,
  19. Tracy Lester7,
  20. Noina Abid12,
  21. Deirdre Cilliers3,4,
  22. Jane A Hurst6,
  23. Jenny E V Morton13,
  24. Elizabeth Sweeney14,
  25. Astrid Weber14,
  26. Louise C Wilson6,
  27. Andrew O M Wilkie1,3,4
  1. 1Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
  2. 2Computational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
  3. 3Department of Clinical Genetics, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
  4. 4Craniofacial Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
  5. 5Department of Craniofacial Surgery, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK
  6. 6North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
  7. 7Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
  8. 8Oxford Biomedical Research Centre, National Institute for Health Research, Oxford, UK
  9. 9Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
  10. 10Department of Plastic and Reconstructive Surgery and Hand Surgery, Erasmus Medical Centre, University Medical Centre Rotterdam, Rotterdam, The Netherlands
  11. 11Department of Bioinformatics, Erasmus Medical Centre, University Medical Centre Rotterdam, Rotterdam, The Netherlands
  12. 12Department of Paediatric Endocrinology, The Royal Belfast Hospital for Sick Children, Belfast, UK
  13. 13Clinical Genetics Unit, Birmingham Women's Hospital NHS Foundation Trust, Birmingham, UK
  14. 14Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, UK
  1. Correspondence to Professor Andrew O M Wilkie, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK; andrew.wilkie{at}


Background Craniosynostosis, the premature fusion of one or more cranial sutures, occurs in ∼1 in 2250 births, either in isolation or as part of a syndrome. Mutations in at least 57 genes have been associated with craniosynostosis, but only a minority of these are included in routine laboratory genetic testing.

Methods We used exome or whole genome sequencing to seek a genetic cause in a cohort of 40 subjects with craniosynostosis, selected by clinical or molecular geneticists as being high-priority cases, and in whom prior clinically driven genetic testing had been negative.

Results We identified likely associated mutations in 15 patients (37.5%), involving 14 different genes. All genes were mutated in single families, except for IL11RA (two families). We classified the other positive diagnoses as follows: commonly mutated craniosynostosis genes with atypical presentation (EFNB1, TWIST1); other core craniosynostosis genes (CDC45, MSX2, ZIC1); genes for which mutations are only rarely associated with craniosynostosis (FBN1, HUWE1, KRAS, STAT3); and known disease genes for which a causal relationship with craniosynostosis is currently unknown (AHDC1, NTRK2). In two further families, likely novel disease genes are currently undergoing functional validation. In 5 of the 15 positive cases, the (previously unanticipated) molecular diagnosis had immediate, actionable consequences for either genetic or medical management (mutations in EFNB1, FBN1, KRAS, NTRK2, STAT3).

Conclusions This substantial genetic heterogeneity, and the multiple actionable mutations identified, emphasises the benefits of exome/whole genome sequencing to identify causal mutations in craniosynostosis cases for which routine clinical testing has yielded negative results.

  • Craniosynostosis
  • Exome/whole genome sequencing
  • Actionable mutation

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  • Contributors KAM, SRFT, JMP, ALF, DJ, SAW, PN, KEMR, EAT, JC, JT, JCT, JACG, IMJM, HL, TL, NA, DC, JAH, JEVM, ES, AW, LCW and AOMW contributed to patient recruitment, genetic or functional work. SJM, SMAS and PJS performed bioinformatics analyses. KAM and AOMW wrote the manuscript, with clinical input from NA, JAH, JEVM, AW and LCW.

  • Funding Core facilities were supported by the WIMM Strategic Alliance (G0902418 and MC_UU_12025). This work was supported by National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme (JCT and AOMW), the Department of Health, UK, Quality, Improvement, Development and Initiative Scheme (QIDIS) (AOMW) and the Wellcome Trust (Project Grant 093329 to AOMW and SRFT, and Senior Investigator Award 102731 to AOMW).

  • Disclaimer The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval London—Riverside Research Ethics Committee (reference 09/H0706/20).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement ES data for samples where we obtained the appropriate consent are available from the ENA under accession number PRJEB17650. Previously unreported mutations, where we have obtained the relevant consent (ie, ZIC1), have been uploaded to the appropriate LOVD 3.0 shared installation locus specific database (Variant ID #0000127941).

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