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High prevalence of CCDC103 p.His154Pro mutation causing primary ciliary dyskinesia disrupts protein oligomerisation and is associated with normal diagnostic investigations
  1. Amelia Shoemark1,
  2. Eduardo Moya2,
  3. Robert A Hirst3,
  4. Mitali P Patel4,
  5. Evelyn A Robson2,
  6. Jane Hayward4,5,
  7. Juliet Scully4,6,
  8. Mahmoud R Fassad4,7,
  9. William Lamb4,
  10. Miriam Schmidts8,9,
  11. Mellisa Dixon1,
  12. Ramila S Patel-King10,
  13. Andrew V Rogers1,11,
  14. Andrew Rutman3,
  15. Claire L Jackson12,13,
  16. Patricia Goggin12,13,
  17. Bruna Rubbo12,13,
  18. Sarah Ollosson1,
  19. Siobhán Carr1,
  20. Woolf Walker12,13,
  21. Beryl Adler14,
  22. Michael R Loebinger11,
  23. Robert Wilson11,
  24. Andrew Bush1,15,
  25. Hywel Williams16,
  26. Christopher Boustred5,
  27. Lucy Jenkins5,
  28. Eamonn Sheridan17,
  29. Eddie M K Chung18,
  30. Christopher M Watson17,
  31. Thomas Cullup5,
  32. Jane S Lucas12,13,
  33. Priti Kenia19,
  34. Christopher O’Callaghan3,20,
  35. Stephen M King10,21,
  36. Claire Hogg1,
  37. Hannah M Mitchison4
  1. 1Department of Paediatric Respiratory Medicine, Royal Brompton and Harefield NHS Trust, National Heart and Lung Institute, London, UK
  2. 2Division of Services for Women and Children, Women's and Newborn Unit Bradford Royal Infirmary, University of Bradford, Bradford, UK
  3. 3Department of Infection, Centre for PCD Diagnosis and Research, Immunity and Inflammation, University of Leicester, Leicester, UK
  4. 4Genetics and Genomic Medicine, University College London, UCL Great Ormond Street Institute of Child Health, London, UK
  5. 5North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children, London, UK
  6. 6Neuroscience and Mental Health Research Institute, School of Medicine and School of Bioscience, Cardiff University, London, UK
  7. 7Human Genetics Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
  8. 8Genome Research Division, Human Genetics Department, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
  9. 9Pediatric Genetics Division, Center for Pediatrics and Adolescent Medicine, University of Freiburg Medical Center, Freiburg, Germany
  10. 10Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, Connecticut, USA
  11. 11Department of Respiratory Medicine, Royal Brompton and Harefield NHS Trust, London, UK
  12. 12Primary Ciliary Dyskinesia Centre, University Hospital Southampton NHS Foundation Trust and Clinical and Experimental Sciences Academic Unit, University of Southampton Faculty of Medicine, Southampton, UK
  13. 13NIHR Southampton Respiratory Biomedical Research Unit, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK
  14. 14Department of Paediatrics, Luton and Dunstable Hospital NHS Trust, Luton, UK
  15. 15Department of Paediatric Respiratory Medicine, National Heart and Lung Institute, Imperial College, London, UK
  16. 16Centre for Translational Omics-GOSgene, Genetics and Genomic Medicine, University College London, Institute of Child Health, London, UK
  17. 17Yorkshire Regional Genetics Service and School of Medicine, University of Leeds, St. James's University Hospital, Leeds, UK
  18. 18Population, Policy and Practice Programme, University College London, UCL Great Ormond Street Institute of Child Health, London, UK
  19. 19Department of Respiratory Paediatrics, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK
  20. 20Infection, Immunity, Inflammation and Physiological Medicine, University College London, Institute of Child Health, London, UK
  21. 21Institute for Systems Genomics, University of Connecticut Health Center, Farmington, Connecticut, USA
  1. Correspondence to Dr Hannah M Mitchison, PUW32, Experimental and Personalised Medicine Section, Genetics and Genomic Medicine Programme, UCL Great Ormond Street, Institute of Child Health, London WC1N 1EH, UK; h.mitchison{at}ucl.ac.uk

Abstract

Rationale Primary ciliary dyskinesia is a genetically heterogeneous inherited condition characterised by progressive lung disease arising from abnormal cilia function. Approximately half of patients have situs inversus. The estimated prevalence of primary ciliary dyskinesia in the UK South Asian population is 1:2265. Early, accurate diagnosis is key to implementing appropriate management but clinical diagnostic tests can be equivocal.

Objectives To determine the importance of genetic screening for primary ciliary dyskinesia in a UK South Asian population with a typical clinical phenotype, where standard testing is inconclusive.

Methods Next-generation sequencing was used to screen 86 South Asian patients who had a clinical history consistent with primary ciliary dyskinesia. The effect of a CCDC103 p.His154Pro missense variant compared with other dynein arm-associated gene mutations on diagnostic/phenotypic variability was tested. CCDC103 p.His154Pro variant pathogenicity was assessed by oligomerisation assay.

Results Sixteen of 86 (19%) patients carried a homozygous CCDC103 p.His154Pro mutation which was found to disrupt protein oligomerisation. Variable diagnostic test results were obtained including normal nasal nitric oxide levels, normal ciliary beat pattern and frequency and a spectrum of partial and normal dynein arm retention. Fifteen (94%) patients or their sibling(s) had situs inversus suggesting CCDC103 p.His154Pro patients without situs inversus are missed.

Conclusions The CCDC103 p.His154Pro mutation is more prevalent than previously thought in the South Asian community and causes primary ciliary dyskinesia that can be difficult to diagnose using pathology-based clinical tests. Genetic testing is critical when there is a strong clinical phenotype with inconclusive standard diagnostic tests.

  • primary ciliary dyskinesia
  • respiratory tract
  • cilia
  • diagnosis
  • CCDC103
  • mutation
  • genetic testing.
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Footnotes

  • Contributors AS, HMM, EAR and EM were responsible for study concept and design. MPP, JH, JS, MRF, WL, HW, CB, LJ, CMW, TC and HMM performed the genetic analyses. RSPK and SMK performed the biochemical analysis. AS, MD, AVR, AR and PG performed electron microscopy. AS, RAH, MD, AVR, CLJ and SO performed cilia cell culture and cilia functional testing. EM, EAR, SC, WW, BA, MRL, BR, RW, AB, ES, JSL, PK, COC and CH provided clinical information. AS, SMK, CH and HMM wrote the manuscript and all authors contributed to the final version. HMM is the guarantor responsible for the overall content.

  • Funding The research is supported by the BEAT-PCD: Better Evidence to Advance Therapeutic options for PCD network (COST Action 1407). AB was supported by the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London. Work by AS is independent research funded by a postdoctoral research fellowship from the National Institute of Health Research and Health Education England. RSPK and SMK are supported by NIH grant GM051293. MS is supported by a Radboudumc Hypatia Tenure Track fellowship, a Radboud University Excellence fellowship, an ERC starting grant (TREATCilia, grant no.716344) and received funding from the German Research Foundation (DFG), collaborative Research Center (CRC) 1140 KIDGEM. This research and the Centre for Translational Omics (GOSgene) is supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. HMM was supported by grants from Action Medical Research (GN2101), Newlife Foundation (10-11/15) and the Great Ormond Street Hospital Children's Charity. Work in Southampton is supported by the NIHR Respiratory Biomedical Research Unit and NIHR Wellcome Trust Clinical Research Facility.

  • Competing interests None declared.

  • Ethics approval London Bloomsbury Research Ethics Committee.

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

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