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
- genetic testing.
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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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