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 language | English |
|---|---|
| Pages (from-to) | 157-166 |
| Number of pages | 10 |
| Journal | Thorax |
| Volume | 73 |
| Issue number | 2 |
| Early online date | 3 Aug 2017 |
| DOIs | |
| Publication status | Published - 1 Feb 2018 |
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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
}
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 journal › Article
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
C2 - 28790179
VL - 73
SP - 157
EP - 166
JO - Thorax
JF - Thorax
SN - 0040-6376
IS - 2
ER -