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 Walker & 17 others Beryl 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

Fingerprint

Kartagener Syndrome
Situs Inversus
Mutation
Routine Diagnostic Tests
Dyneins
Genetic Testing
Proteins
Phenotype
Clinical Pathology
Cilia
Nose
Population
Lung Diseases
Virulence
Siblings
Early Diagnosis
Nitric Oxide
Genes

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

Cite this

Shoemark, Amelia ; Moya, Eduardo ; Hirst, Robert A. ; Patel, Mitali ; Robson, Evelyn A. ; Hayward, Jane ; Scully, Juliet ; Fassad, Mahmoud R. ; Lamb, William ; Schmidts, Miriam ; Dixon, Mellisa ; Patel-King, Ramila S. ; Rogers, Andrew V. ; Rutman, Andrew ; Jackson, Claire L. ; Goggin, Patricia ; Rubbo, Bruna ; Ollosson, Sarah ; Carr, Siobhán ; Walker, Woolf ; Adler, Beryl ; Loebinger, Michael ; Wilson, Robert ; Bush, Andrew ; Williams, Hywel ; Boustred, Christopher ; Jenkins, Lucy ; Sheridan, Eamonn ; Chung, Eddie M. K. ; Watson, Christopher M. ; Cullup, Thomas ; Lucas, Jane S ; Kenia, Priti ; O'Callaghan, Christopher A. ; King, Stephen M. ; Hogg, Claire ; Mitchison, Hannah M. / High prevalence of CCDC103 p.His154Pro mutation causing primary ciliary dyskinesia disrupts protein oligomerisation and is associated with normal diagnostic investigations. In: Thorax. 2018 ; Vol. 73, No. 2. pp. 157-166.
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title = "High prevalence of CCDC103 p.His154Pro mutation causing primary ciliary dyskinesia disrupts protein oligomerisation and is associated with normal diagnostic investigations",
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.",
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",
author = "Amelia Shoemark and Eduardo Moya and Hirst, {Robert A.} and Mitali Patel and Robson, {Evelyn A.} and Jane Hayward and Juliet Scully and Fassad, {Mahmoud R.} and William Lamb and Miriam Schmidts and Mellisa Dixon and Patel-King, {Ramila S.} and Rogers, {Andrew V.} and Andrew Rutman and Jackson, {Claire L.} and Patricia Goggin and Bruna Rubbo and Sarah Ollosson and Siobh{\'a}n Carr and Woolf Walker and Beryl Adler and Michael Loebinger and Robert Wilson and Andrew Bush and Hywel Williams and Christopher Boustred and Lucy Jenkins and Eamonn Sheridan and Chung, {Eddie M. K.} and Watson, {Christopher M.} and Thomas Cullup and Lucas, {Jane S} and Priti Kenia and O'Callaghan, {Christopher A.} and King, {Stephen M.} and Claire Hogg and Mitchison, {Hannah M.}",
note = "Sources of support: The research is supported by the BEAT-PCD: Better Evidence to Advance Therapeutic options for PCD network (COST Action 1407). A.B. 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 A.S. is independent research funded by a postdoctoral research fellowship from the National Institute of Health Research and Health Education England. R.S.P-K. and S.M.K. are supported by NIH grant GM051293. M.S. is supported by a Radboudumc Hypatia Tenure Track fellowship, a Radboud University Excellence fellowship, an ERC starting grant (TREATCilia) 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. H.M.M. 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 NIHR Respiratory Biomedical Research Unit and NIHR Wellcome Trust Clinical Research Facility.",
year = "2018",
month = "2",
day = "1",
doi = "10.1136/thoraxjnl-2017-209999",
language = "English",
volume = "73",
pages = "157--166",
journal = "Thorax",
issn = "0040-6376",
publisher = "BMJ Publishing Group",
number = "2",

}

Shoemark, A, Moya, E, Hirst, RA, Patel, M, Robson, EA, Hayward, J, Scully, J, Fassad, MR, Lamb, W, Schmidts, M, Dixon, M, Patel-King, RS, Rogers, AV, Rutman, A, Jackson, CL, Goggin, P, Rubbo, B, Ollosson, S, Carr, S, Walker, W, Adler, B, Loebinger, M, Wilson, R, Bush, A, Williams, H, Boustred, C, Jenkins, L, Sheridan, E, Chung, EMK, Watson, CM, Cullup, T, Lucas, JS, Kenia, P, O'Callaghan, CA, King, SM, Hogg, C & Mitchison, HM 2018, 'High prevalence of CCDC103 p.His154Pro mutation causing primary ciliary dyskinesia disrupts protein oligomerisation and is associated with normal diagnostic investigations', Thorax, vol. 73, no. 2, pp. 157-166. https://doi.org/10.1136/thoraxjnl-2017-209999

High prevalence of CCDC103 p.His154Pro mutation causing primary ciliary dyskinesia disrupts protein oligomerisation and is associated with normal diagnostic investigations. / Shoemark, Amelia; Moya, Eduardo ; Hirst, Robert A. ; Patel, Mitali; Robson, Evelyn A. ; Hayward, Jane ; Scully, Juliet; Fassad, Mahmoud R. ; Lamb, William ; Schmidts, Miriam ; Dixon, Mellisa; Patel-King, Ramila S. ; Rogers, Andrew V.; Rutman, Andrew ; Jackson, Claire L. ; Goggin, Patricia ; Rubbo, Bruna ; Ollosson, Sarah; Carr, Siobhán ; Walker, Woolf ; Adler, Beryl ; Loebinger, Michael; Wilson, Robert; Bush, Andrew; Williams, Hywel ; Boustred, Christopher ; Jenkins, Lucy ; Sheridan, Eamonn ; Chung, Eddie M. K. ; Watson, Christopher M. ; Cullup, Thomas; Lucas, Jane S ; Kenia, Priti ; O'Callaghan, Christopher A.; King, Stephen M. ; Hogg, Claire; Mitchison, Hannah M. (Lead / Corresponding author).

In: Thorax, Vol. 73, No. 2, 01.02.2018, p. 157-166.

Research output: Contribution to journalArticle

TY - JOUR

T1 - High prevalence of CCDC103 p.His154Pro mutation causing primary ciliary dyskinesia disrupts protein oligomerisation and is associated with normal diagnostic investigations

AU - Shoemark, Amelia

AU - Moya, Eduardo

AU - Hirst, Robert A.

AU - Patel, Mitali

AU - Robson, Evelyn A.

AU - Hayward, Jane

AU - Scully, Juliet

AU - Fassad, Mahmoud R.

AU - Lamb, William

AU - Schmidts, Miriam

AU - Dixon, Mellisa

AU - Patel-King, Ramila S.

AU - Rogers, Andrew V.

AU - Rutman, Andrew

AU - Jackson, Claire L.

AU - Goggin, Patricia

AU - Rubbo, Bruna

AU - Ollosson, Sarah

AU - Carr, Siobhán

AU - Walker, Woolf

AU - Adler, Beryl

AU - Loebinger, Michael

AU - Wilson, Robert

AU - Bush, Andrew

AU - Williams, Hywel

AU - Boustred, Christopher

AU - Jenkins, Lucy

AU - Sheridan, Eamonn

AU - Chung, Eddie M. K.

AU - Watson, Christopher M.

AU - Cullup, Thomas

AU - Lucas, Jane S

AU - Kenia, Priti

AU - O'Callaghan, Christopher A.

AU - King, Stephen M.

AU - Hogg, Claire

AU - Mitchison, Hannah M.

N1 - Sources of support: The research is supported by the BEAT-PCD: Better Evidence to Advance Therapeutic options for PCD network (COST Action 1407). A.B. 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 A.S. is independent research funded by a postdoctoral research fellowship from the National Institute of Health Research and Health Education England. R.S.P-K. and S.M.K. are supported by NIH grant GM051293. M.S. is supported by a Radboudumc Hypatia Tenure Track fellowship, a Radboud University Excellence fellowship, an ERC starting grant (TREATCilia) 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. H.M.M. 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 NIHR Respiratory Biomedical Research Unit and NIHR Wellcome Trust Clinical Research Facility.

PY - 2018/2/1

Y1 - 2018/2/1

N2 - 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.

AB - 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.

KW - primary ciliary dyskinesia

KW - respiratory tract

KW - cilia

KW - diagnosis

KW - CCDC103

KW - mutation

KW - genetic testing

KW - genetic testing.

KW - Mutation/genetics

KW - Humans

KW - Child, Preschool

KW - Kartagener Syndrome/ethnology

KW - Male

KW - United Kingdom

KW - Microtubule-Associated Proteins/genetics

KW - Young Adult

KW - Asian Continental Ancestry Group/genetics

KW - Pakistan/ethnology

KW - Adolescent

KW - Adult

KW - Female

KW - Child

KW - Cohort Studies

UR - http://www.scopus.com/inward/record.url?scp=85029216510&partnerID=8YFLogxK

U2 - 10.1136/thoraxjnl-2017-209999

DO - 10.1136/thoraxjnl-2017-209999

M3 - Article

VL - 73

SP - 157

EP - 166

JO - Thorax

JF - Thorax

SN - 0040-6376

IS - 2

ER -