Diagnostic value of exome and whole genome sequencing in craniosynostosis

doi:10.1136/jmedgenet-2016-104215

. 2017 Apr;54(4):260-268.

doi: 10.1136/jmedgenet-2016-104215. Epub 2016 Nov 24.

Diagnostic value of exome and whole genome sequencing in craniosynostosis

Kerry A Miller¹, Stephen R F Twigg¹, Simon J McGowan², Julie M Phipps^{1

3}, Aimée L Fenwick¹, David Johnson⁴, Steven A Wall⁴, Peter Noons⁵, Katie E M Rees⁶, Elizabeth A Tidey⁶, Judith Craft⁷, John Taylor⁷, Jenny C Taylor^{8

9}, Jacqueline A C Goos¹⁰, Sigrid M A Swagemakers¹¹, Irene M J Mathijssen¹⁰, Peter J van der Spek¹¹, Helen Lord⁷, Tracy Lester⁷, Noina Abid¹², Deirdre Cilliers^{3

4}, Jane A Hurst⁶, Jenny E V Morton¹³, Elizabeth Sweeney¹⁴, Astrid Weber¹⁴, Louise C Wilson⁶, Andrew O M Wilkie^{1

3

4}

Affiliations

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.
¹¹ Department of Bioinformatics, Erasmus Medical Centre, University Medical Centre Rotterdam, Rotterdam, The 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.

PMID: 27884935
PMCID: PMC5366069
DOI: 10.1136/jmedgenet-2016-104215

Diagnostic value of exome and whole genome sequencing in craniosynostosis

Kerry A Miller et al. J Med Genet. 2017 Apr.

. 2017 Apr;54(4):260-268.

doi: 10.1136/jmedgenet-2016-104215. Epub 2016 Nov 24.

Authors

Affiliations

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.
¹¹ Department of Bioinformatics, Erasmus Medical Centre, University Medical Centre Rotterdam, Rotterdam, The 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.

PMID: 27884935
PMCID: PMC5366069
DOI: 10.1136/jmedgenet-2016-104215

Abstract

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.

Keywords: Actionable mutation; Craniosynostosis; Exome/whole genome sequencing.

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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Conflict of interest statement

Competing interests: None declared.

Figures

**Figure 1**
Family pedigrees, clinical photographs/3D-CT scans and sequencing traces of families with mutations identified in *FBN1* (A), *EFNB1* (B) and *STAT3* (C). Each panel shows the location of the mutation (red line) within the gene structure (exons in blue), family pedigree (affected individuals are in black, black arrow depicts the proband and individuals selected for exome sequence/whole genome sequence are indicated with a red asterisk), sequence traces of indicated individuals (red arrow indicates position of mutation) and clinical photographs (B) and 3D-CT scans (C) of affected individuals. Note facial asymmetry associated with right unicoronal synostosis in patient with *EFNB1* mutation (B); there is moderate hypertelorism, but the grooving of the nasal tip usually observed in craniofrontonasal syndrome is absent. In the patient with the *STAT3* mutation (C), images with soft tissue windows (left and centre) show exorbitism, mid-face hypoplasia and vertex bulge; image with bone windows (right) shows fusion of all sutures of the skull vault.

**Figure 2**
Identified mutations and their association within the classification of craniosynostosis-associated genes proposed by Twigg and Wilkie.

See this image and copyright information in PMC

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[1] Gilissen C, Hehir-Kwa JY, Thung DT, van de Vorst M, van Bon BW, Willemsen MH, Kwint M, Janssen IM, Hoischen A, Schenck A, Leach R, Klein R, Tearle R, Bo T, Pfundt R, Yntema HG, de Vries BB, Kleefstra T, Brunner HG, Vissers LE, Veltman JA. Genome sequencing identifies major causes of severe intellectual disability. Nature 2014;511:344–7. 10.1038/nature13394 - DOI - PubMed

[2] Gilissen C, Hehir-Kwa JY, Thung DT, van de Vorst M, van Bon BW, Willemsen MH, Kwint M, Janssen IM, Hoischen A, Schenck A, Leach R, Klein R, Tearle R, Bo T, Pfundt R, Yntema HG, de Vries BB, Kleefstra T, Brunner HG, Vissers LE, Veltman JA. Genome sequencing identifies major causes of severe intellectual disability. Nature 2014;511:344–7. 10.1038/nature13394 - DOI - PubMed

[3] Taylor JC, Martin HC, Lise S, Broxholme J, Cazier JB, Rimmer A, Kanapin A, Lunter G, Fiddy S, Allan C, Aricescu AR, Attar M, Babbs C, Becq J, Beeson D, Bento C, Bignell P, Blair E, Buckle VJ, Bull K, Cais O, Cario H, Chapel H, Copley RR, Cornall R, Craft J, Dahan K, Davenport EE, Dendrou C, Devuyst O, Fenwick AL, Flint J, Fugger L, Gilbert RD, Goriely A, Green A, Greger IH, Grocock R, Gruszczyk AV, Hastings R, Hatton E, Higgs D, Hill A, Holmes C, Howard M, Hughes L, Humburg P, Johnson D, Karpe F, Kingsbury Z, Kini U, Knight JC, Krohn J, Lamble S, Langman C, Lonie L, Luck J, McCarthy D, McGowan SJ, McMullin MF, Miller KA, Murray L, Nemeth AH, Nesbit MA, Nutt D, Ormondroyd E, Oturai AB, Pagnamenta A, Patel SY, Percy M, Petousi N, Piazza P, Piret SE, Polanco-Echeverry G, Popitsch N, Powrie F, Pugh C, Quek L, Robbins PA, Robson K, Russo A, Sahgal N, van Schouwenburg PA, Schuh A, Silverman E, Simmons A, Sorensen PS, Sweeney E, Taylor J, Thakker RV, Tomlinson I, Trebes A, Twigg SRF, Uhlig HH, Vyas P, Vyse T, Wall SA, Watkins H, Whyte MP, Witty L, Wright B, Yau C, Buck D, Humphray S, Ratcliffe PJ, Bell JI, Wilkie AOM, Bentley D, Donnelly P, McVean G. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nat Genet 2015;47:717–26. 10.1038/ng.3304 - DOI - PMC - PubMed

[4] Taylor JC, Martin HC, Lise S, Broxholme J, Cazier JB, Rimmer A, Kanapin A, Lunter G, Fiddy S, Allan C, Aricescu AR, Attar M, Babbs C, Becq J, Beeson D, Bento C, Bignell P, Blair E, Buckle VJ, Bull K, Cais O, Cario H, Chapel H, Copley RR, Cornall R, Craft J, Dahan K, Davenport EE, Dendrou C, Devuyst O, Fenwick AL, Flint J, Fugger L, Gilbert RD, Goriely A, Green A, Greger IH, Grocock R, Gruszczyk AV, Hastings R, Hatton E, Higgs D, Hill A, Holmes C, Howard M, Hughes L, Humburg P, Johnson D, Karpe F, Kingsbury Z, Kini U, Knight JC, Krohn J, Lamble S, Langman C, Lonie L, Luck J, McCarthy D, McGowan SJ, McMullin MF, Miller KA, Murray L, Nemeth AH, Nesbit MA, Nutt D, Ormondroyd E, Oturai AB, Pagnamenta A, Patel SY, Percy M, Petousi N, Piazza P, Piret SE, Polanco-Echeverry G, Popitsch N, Powrie F, Pugh C, Quek L, Robbins PA, Robson K, Russo A, Sahgal N, van Schouwenburg PA, Schuh A, Silverman E, Simmons A, Sorensen PS, Sweeney E, Taylor J, Thakker RV, Tomlinson I, Trebes A, Twigg SRF, Uhlig HH, Vyas P, Vyse T, Wall SA, Watkins H, Whyte MP, Witty L, Wright B, Yau C, Buck D, Humphray S, Ratcliffe PJ, Bell JI, Wilkie AOM, Bentley D, Donnelly P, McVean G. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nat Genet 2015;47:717–26. 10.1038/ng.3304 - DOI - PMC - PubMed

[7] Boulet SL, Rasmussen SA, Honein MA. A population-based study of craniosynostosis in metropolitan Atlanta, 1989-2003. Am J Med Genet A 2008;146A:984–91. 10.1002/ajmg.a.32208 - DOI - PubMed

[8] Boulet SL, Rasmussen SA, Honein MA. A population-based study of craniosynostosis in metropolitan Atlanta, 1989-2003. Am J Med Genet A 2008;146A:984–91. 10.1002/ajmg.a.32208 - DOI - PubMed

[9] Lajeunie E, Le Merrer M, Bonaiti-Pellie C, Marchac D, Renier D. Genetic study of nonsyndromic coronal craniosynostosis. Am J Med Genet 1995;55:500–4. 10.1002/ajmg.1320550422 - DOI - PubMed

[10] Lajeunie E, Le Merrer M, Bonaiti-Pellie C, Marchac D, Renier D. Genetic study of nonsyndromic coronal craniosynostosis. Am J Med Genet 1995;55:500–4. 10.1002/ajmg.1320550422 - DOI - PubMed

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Diagnostic value of exome and whole genome sequencing in craniosynostosis

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Diagnostic value of exome and whole genome sequencing in craniosynostosis

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