High prevalence of CCDC103 p.His154Pro mutation causing primary ciliary dyskinesia disrupts protein oligomerisation and is associated with normal diagnostic investigations

Amelia Shoemark, Eduardo Moya, Robert A. Hirst, Mitali Patel, Evelyn A. Robson, Jane Hayward, Juliet Scully, Mahmoud R. Fassad, William Lamb, Miriam Schmidts, Mellisa Dixon, Ramila S. Patel-King, Andrew V. Rogers, Andrew Rutman, Claire L. Jackson, Patricia Goggin, Bruna Rubbo, Sarah Ollosson, Siobhán Carr, Woolf WalkerBeryl Adler, Michael Loebinger, Robert Wilson, Andrew Bush, Hywel Williams, Christopher Boustred, Lucy Jenkins, Eamonn Sheridan, Eddie M. K. Chung, Christopher M. Watson, Thomas Cullup, Jane S Lucas, Priti Kenia, Christopher A. O'Callaghan, Stephen M. King, Claire Hogg, Hannah M. Mitchison

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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.

Original languageEnglish
Pages (from-to)157-166
Number of pages10
JournalThorax
Volume73
Issue number2
Early online date3 Aug 2017
DOIs
Publication statusPublished - 1 Feb 2018

Keywords

  • primary ciliary dyskinesia
  • respiratory tract
  • cilia
  • diagnosis
  • CCDC103
  • mutation
  • genetic testing
  • genetic testing.
  • Mutation/genetics
  • Humans
  • Child, Preschool
  • Kartagener Syndrome/ethnology
  • Male
  • United Kingdom
  • Microtubule-Associated Proteins/genetics
  • Young Adult
  • Asian Continental Ancestry Group/genetics
  • Pakistan/ethnology
  • Adolescent
  • Adult
  • Female
  • Child
  • Cohort Studies

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    Shoemark, A., Moya, E., Hirst, R. A., Patel, M., Robson, E. A., Hayward, J., Scully, J., Fassad, M. R., Lamb, W., Schmidts, M., Dixon, M., Patel-King, R. S., Rogers, A. V., Rutman, A., Jackson, C. L., Goggin, P., Rubbo, B., Ollosson, S., Carr, S., ... Mitchison, H. M. (2018). High prevalence of CCDC103 p.His154Pro mutation causing primary ciliary dyskinesia disrupts protein oligomerisation and is associated with normal diagnostic investigations. Thorax, 73(2), 157-166. https://doi.org/10.1136/thoraxjnl-2017-209999