title: Diagnostic value of exome and whole genome sequencing in craniosynostosis.
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 forIL11RA(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 inEFNB1,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.
authors.affiliation: Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Kerry A
authors.identifier: 0000-0003-2278-155X
authors.initials: KA
authors.lastname: Miller
authors.affiliation: Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Stephen R F
authors.initials: SR
authors.lastname: Twigg
authors.affiliation: Computational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: McGowan
authors.affiliation: Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.|Department of Clinical Genetics, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Phipps
authors.affiliation: Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Aimée L
authors.initials: AL
authors.lastname: Fenwick
authors.affiliation: Craniofacial Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
authors.forename: David
authors.initials: D
authors.lastname: Johnson
authors.affiliation: Craniofacial Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Wall
authors.affiliation: Department of Craniofacial Surgery, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Noons
authors.affiliation: North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
authors.forename: Katie E M
authors.initials: KE
authors.lastname: Rees
authors.affiliation: North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Tidey
authors.affiliation: Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
authors.forename: Judith
authors.initials: J
authors.lastname: Craft
authors.affiliation: Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
authors.forename: John
authors.initials: J
authors.lastname: Taylor
authors.affiliation: Oxford Biomedical Research Centre, National Institute for Health Research, Oxford, UK.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Taylor
authors.affiliation: Department of Plastic and Reconstructive Surgery and Hand Surgery, Erasmus Medical Centre, University Medical Centre Rotterdam, Rotterdam, The Netherlands.
authors.forename: Jacqueline A C
authors.initials: JA
authors.lastname: Goos
authors.affiliation: Department of Bioinformatics, Erasmus Medical Centre, University Medical Centre Rotterdam, Rotterdam, The Netherlands.
authors.forename: Sigrid M A
authors.initials: SM
authors.lastname: Swagemakers
authors.affiliation: Department of Plastic and Reconstructive Surgery and Hand Surgery, Erasmus Medical Centre, University Medical Centre Rotterdam, Rotterdam, The Netherlands.
authors.forename: Irene M J
authors.initials: IM
authors.lastname: Mathijssen
authors.affiliation: Department of Bioinformatics, Erasmus Medical Centre, University Medical Centre Rotterdam, Rotterdam, The Netherlands.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: van der Spek
authors.affiliation: Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Lord
authors.affiliation: Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
authors.forename: Tracy
authors.initials: T
authors.lastname: Lester
authors.affiliation: Department of Paediatric Endocrinology, The Royal Belfast Hospital for Sick Children, Belfast, UK.
authors.forename: Noina
authors.initials: N
authors.lastname: Abid
authors.affiliation: Department of Clinical Genetics, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.|Craniofacial Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
authors.forename: Deirdre
authors.initials: D
authors.lastname: Cilliers
authors.affiliation: North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Hurst
authors.affiliation: Clinical Genetics Unit, Birmingham Women's Hospital NHS Foundation Trust, Birmingham, UK.
authors.forename: Jenny E V
authors.initials: JE
authors.lastname: Morton
authors.affiliation: Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sweeney
authors.affiliation: Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
authors.forename: Astrid
authors.initials: A
authors.lastname: Weber
authors.affiliation: North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
authors.forename: Louise C
authors.initials: LC
authors.lastname: Wilson
authors.affiliation: Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.|Department of Clinical Genetics, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.|Craniofacial Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
authors.forename: Andrew O M
authors.initials: AO
authors.lastname: Wilkie
mesh_terms: D003398:Craniosynostoses / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D059472:Exome / Q000235:genetics; D005820:Genetic Testing; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D011237:Predictive Value of Tests
chemical_list: D009363:Neoplasm Proteins
keywords: Actionable mutation; Craniosynostosis; Exome/whole genome sequencing