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Genotype and clinical care correlations in craniosynostosis: Findings from a cohort of 630 Australian and New Zealand patients

Authors

  • T. Roscioli,

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    • Tony Roscioli is a clinical geneticist with an interest in craniofacial, immunodeficiency and neuronal migration disorders, and the application of clinical genomics to gene identification and patient care.
  • G. Elakis,

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    • George Elakis is a senior molecular scientist with 23 years laboratory experience. His interests include the molecular genetics of craniofacial and intellectual disability disorders, next generation sequencing and computational laboratory support networks.
  • T.C. Cox,

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    • Timothy C. Cox is Professor and Laurel Endowed Chair in Craniofacial Research in the University of Washington's Department of Pediatrics (Division of Craniofacial Medicine) and the Center for Developmental Biology and Regenerative Medicine at Seattle Children's Research Institute. He research interests lie in understanding genetic and epigenetic contributions to craniofacial development and dysmorphism.
  • D.J. Moon,

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    • David Moon is a craniofacial surgeon who is working at Sydney Children's Hospital to gain additional clinical experience in plastic surgery.
  • H. Venselaar,

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    • Hanka Venselaar is a structural bioinformatician at the CMBI in Nijmegen, the Netherlands. She focuses on the analysis of mutations and their effects on protein structures.
  • A.M. Turner,

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    • Anne Turner is the director of the Department of Medical Genetics at Sydney Children's hospital. She has an interest in dysmorphology, eye and craniofacial disorders.
  • T. Le,

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    • Trang Le is a molecular scientist working in the South Eastern Area Laboratory Services molecular diagnostic laboratory.
  • E. Hackett,

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    • Emma Hackett is a molecular scientist working in the South Eastern Area Laboratory Services molecular diagnostic laboratory and a senior member of the next generation sequencing diagnostic service.
  • E. Haan,

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    • Eric Haan is a clinical geneticist in the South Australian Clinical Genetics Service, a unit of SA Pathology based at Women's and Children's Hospital, Adelaide and a Clinical Affiliate Professor in the Department of Paediatrics, University of Adelaide. Academic interests include the genetics of intellectual disability and cerebral palsy, and the causes and prevention of genetic disorders and birth defects.
  • A. Colley,

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    • Alison Colley is the director of the Department of Medical Genetics at Liverpool hospital and she has expertise in dysmorphology.
  • D. Mowat,

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    • David Mowat is a clinical geneticist at Sydney Children's Hospital with an interest in syndrome diagnosis.
  • L. Worgan,

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    • Lisa Worgan is a clinical geneticist at the Department of Medical Genetics at Liverpool hospital and she has expertise in dysmorphology.
  • E.P. Kirk,

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    • Edwin Kirk is a clinical geneticist working at Sydney Children's Hospital. His research interests include the genetics of congenital heart disease and of facial clefting.
  • R. Sachdev,

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    • Rani Sachdev is a clinical geneticist working at Sydney Children's Hospital. Her interests include the genetics of epileptic encephalopathies and clinical dysmorphology.
  • E. Thompson,

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    • Elizabeth Thompson is a Clinical geneticist with the South Australian Clinical Genetics Service based at the Women's and Children's Hospital. Her main research interests include dysmorphology and skeletal dysplasias. She is an Associate Professor with the Department of Paediatrics in the University of Adelaide.
  • M. Gabbett,

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    • Michael Gabbett is a senior staff specialist in clinical genetics at the Royal Brisbane & Women's Hospital, Australia.
  • J. McGaughran,

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    • Julie McGaughran is a clinical geneticist with an interest in dysmorphology and cardiac genetics. She is the director of Genetic health Queensland and a member of the council of ESHG.
  • K. Gibson,

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    • Kate Gibson is a Clinical Geneticist working in the South Island Hub of Genetic Health Service NZ.
  • M. Gattas,

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    • Michael Gattas is a Clinical Geneticist with Genetic Health Queensland, and in private practice in Brisbane, Australia.
  • M-L. Freckmann,

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    • Mary-Louise Freckmann is a clinical geneticist who has an interest in clinical dysmorphology.
  • J. Dixon,

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    • Joanne Dixon is the National Clinical Director, Genetic Health Service NZ. She has an interest in the provision and quality assessment of clinical genetic services.
  • L. Hoefsloot,

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    • Lies Hoefsloot is a clinical molecular geneticist working at the Nijmegen molecular diagnostic laboratory. Her expertise includes the provision of molecular and next generation sequencing diagnostic services.
  • M. Field,

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    • Michael Field is a clinical geneticist working primarily in the area of X linked intellectual disability (XLID) as part of the GOLD service. The service has had considerable success with the diagnosis and management of families with XLID.
  • A. Hackett,

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    • Anna Hackett is a clinical geneticist working primarily in the area of X linked intellectual disability (XLID) as director of the GOLD service.
  • B. Kamien,

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    • Benjamin Kamien is a clinical geneticist at Hunter Genetics. His clinical and research areas of interest include dysmorphology, Opitz syndrome, and overgrowth syndromes.
  • M. Edwards,

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    • Matthew Edwards is a clinical geneticist with a long-standing interest in dysmorphology.
  • L.C. Adès,

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    • Lesley Ades is a clinical geneticist at the Children's hospital at Westmead with an interest in connective tissue disorders.
  • F.A. Collins,

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    • Felicity Collins is Head of Department of Clinical Geneticis at the Children's hospital at Westmead. Her interests are in clinical dysmorphology, connective tissue disorders, skeletal dysplasias and prenatal diagnosis.
  • M.J. Wilson,

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    • Meredith Wilson is a clinical geneticist based at Children's Hospital Westmead, Sydney. Dr. Wilson has more than 25 years' experience in clinical genetics practice, with an emphasis on clinical dysmorphology. Dr. Wilson has contributed to a number of publications regarding clinical and molecular aspects of syndrome diagnosis.
  • R. Savarirayan,

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    • Ravi Savarirayan is a clinical geneticist with expertise in skeletal dysplasias and a research interest in the targeted management of genetic disorders.
  • T.Y. Tan,

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    • Tiong Yang Tan is a clinical geneticist with research interest in the developmental mechanisms underpinning dysmorphology and genetic syndromes.
  • D.J. Amor,

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    • David Amor is a clinical geneticist and Director of Victorian Clinical Genetics Services. His special interests include chromosome biology, the identification of genes for rare disorders, and genetic factors associated with assisted reproduction.
  • G. McGIllivray,

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    • George McGillivray is a clinical geneticist working in clinical practice in Melbourne Australia. He previously consulted in the Craniofacial Unit at the Royal Children's Hospital. He currently consults at the perinatal clinics at the Royal Women's Hospital and the Mercy Hospital for Women with a focus on prenatal diagnosis and in the Neurogenetics Clinic at the Royal Children's Hospital.
  • S.M. White,

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    • Susan White is a clinical geneticist in Melbourne, Australia with a research interest in dysmorphic syndromes. She assists in the curation of the POSSUMweb dysmorphology database.
  • I.A. Glass,

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    • Ian Glass is a medical geneticist at the University of Washington, Seattle with a long-standing interest in understanding genetic disorders of the skeleton and cranium and contributed to this work thorough his efforts in phenotyping, genetic mapping and gene identification.
  • D.J. David,

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    • David John David is Clinical Professor of Cranio Maxillofacial Surgery, University of Adelaide, Clinical Professor Macquarie University and Head of Australian Cranio Facial Unit, WCH.
  • P.J. Anderson,

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    • Peter Anderson is Associate Professor at the University of Adelaide, and Director of Research at the Australian Craniofacial Unit. He is currently the President of the Asia Pacific Craniofacial Association and is an Active member of the International Society of Craniofacial surgeons.
  • M. Gianoutsos,

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    • Mark Gianoutsos is the Head of Department of the Sydney Craniofacial Unit at the Sydney Children's Hospital and the Plastic and Craniofacial Research Unit, University of New South Wales. He trained in Craniofacial Surgery at New York University and Is a Founding Member of the Australian and New Zealand Society of Cranio Maxillo Facial Surgeons and a Member of the International Society of Craniofacial Surgeons.
  • M.F. Buckley

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    • Michael Buckley is the director of the SEALS molecular and cytogenetics laboratory. He has an interest in craniofacial diseases, gene identification and the provision of next generation sequencing for clinical services.

  • The authors did not have a conflict of interest regarding this study.

Correspondence to: Dr. T. Roscioli, School of Women's and Children's Health, University of New South Wales, Sydney, NSW 2013, Australia. E-mail: tony.roscioli@sesiahs.health.nsw.gov.au

Abstract

Craniosynostosis is one of the most common craniofacial disorders encountered in clinical genetics practice, with an overall incidence of 1 in 2,500. Between 30% and 70% of syndromic craniosynostoses are caused by mutations in hotspots in the fibroblast growth factor receptor (FGFR) genes or in the TWIST1 gene with the difference in detection rates likely to be related to different study populations within craniofacial centers. Here we present results from molecular testing of an Australia and New Zealand cohort of 630 individuals with a diagnosis of craniosynostosis. Data were obtained by Sanger sequencing of FGFR1, FGFR2, and FGFR3 hotspot exons and the TWIST1 gene, as well as copy number detection of TWIST1. Of the 630 probands, there were 231 who had one of 80 distinct mutations (36%). Among the 80 mutations, 17 novel sequence variants were detected in three of the four genes screened. In addition to the proband cohort there were 96 individuals who underwent predictive or prenatal testing as part of family studies. Dysmorphic features consistent with the known FGFR1-3/TWIST1-associated syndromes were predictive for mutation detection. We also show a statistically significant association between splice site mutations in FGFR2 and a clinical diagnosis of Pfeiffer syndrome, more severe clinical phenotypes associated with FGFR2 exon 10 versus exon 8 mutations, and more frequent surgical procedures in the presence of a pathogenic mutation. Targeting gene hot spot areas for mutation analysis is a useful strategy to maximize the success of molecular diagnosis for individuals with craniosynostosis. © 2013 Wiley Periodicals, Inc.

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