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Diagnostic value of exome and whole genome sequencing in craniosynostosis.

Authors
  • Miller, Kerry A1
  • Twigg, Stephen R F1
  • McGowan, Simon J2
  • Phipps, Julie M1, 3
  • Fenwick, Aimée L1
  • Johnson, David4
  • Wall, Steven A4
  • Noons, Peter5
  • Rees, Katie E M6
  • Tidey, Elizabeth A6
  • Craft, Judith7
  • Taylor, John7
  • Taylor, Jenny C8, 9
  • Goos, Jacqueline A C10
  • Swagemakers, Sigrid M A11
  • Mathijssen, Irene M J10
  • van der Spek, Peter J11
  • Lord, Helen7
  • Lester, Tracy7
  • Abid, Noina12
  • And 7 more
  • 1 Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • 2 Computational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • 3 Department of Clinical Genetics, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
  • 4 Craniofacial Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
  • 5 Department of Craniofacial Surgery, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK.
  • 6 North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
  • 7 Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
  • 8 Oxford Biomedical Research Centre, National Institute for Health Research, Oxford, UK.
  • 9 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
  • 10 Department of Plastic and Reconstructive Surgery and Hand Surgery, Erasmus Medical Centre, University Medical Centre Rotterdam, Rotterdam, The Netherlands. , (Netherlands)
  • 11 Department of Bioinformatics, Erasmus Medical Centre, University Medical Centre Rotterdam, Rotterdam, The Netherlands. , (Netherlands)
  • 12 Department of Paediatric Endocrinology, The Royal Belfast Hospital for Sick Children, Belfast, UK.
  • 13 Clinical Genetics Unit, Birmingham Women's Hospital NHS Foundation Trust, Birmingham, UK.
  • 14 Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
Type
Published Article
Journal
Journal of Medical Genetics
Publisher
BMJ
Publication Date
Apr 01, 2017
Volume
54
Issue
4
Pages
260–268
Identifiers
DOI: 10.1136/jmedgenet-2016-104215
PMID: 27884935
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. 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. 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). 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

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