Background Primary ciliary dyskinesia (PCD), a genetically heterogeneous condition enriched in some consanguineous populations, results from recessive mutations affecting cilia biogenesis and motility. Currently, diagnosis requires multiple expert tests.
Methods The diagnostic utility of multigene panel next-generation sequencing (NGS) was evaluated in 161 unrelated families from multiple population ancestries.
Results Most (82%) families had affected individuals with biallelic or hemizygous (75%) or single (7%) pathogenic causal alleles in known PCD genes. Loss-of-function alleles dominate (73% frameshift, stop-gain, splice site), most (58%) being homozygous, even in non-consanguineous families. Although 57% (88) of the total 155 diagnostic disease variants were novel, recurrent mutations and mutated genes were detected. These differed markedly between white European (52% of families carry DNAH5 or DNAH11 mutations), Arab (42% of families carry CCDC39 or CCDC40 mutations) and South Asian (single LRRC6 or CCDC103 mutations carried in 36% of families) patients, revealing a striking genetic stratification according to population of origin in PCD. Genetics facilitated successful diagnosis of 81% of families with normal or inconclusive ultrastructure and 67% missing prior ultrastructure results.
Conclusions This study shows the added value of high-throughput targeted NGS in expediting PCD diagnosis. Therefore, there is potential significant patient benefit in wider and/or earlier implementation of genetic screening.
- primary ciliary dyskinesia
- mutation spectrum
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Correction notice This article has been corrected since it was published Online First. Affiliation 22 has been corrected.
Contributors MRF, MP, TC, JH, LJ, DJM-R, CMW, HM and HMM performed the genetic and bioinformatic analysis and analysed the genetics data. AS, MD, AVR, SO, CJ, PG, RH, AR, JT, AP and SL were involved in generating and analysing clinical functional tests. AS, MD, AVR, PG, AR and AP performed cilia ultrastructural analysis. MRF, PA, EM, PC, COC, RW, SC, WW, HM, WS, LP, CC, ML, EMKC, PK, NR, NF, JSL, CH and HMM ascertained patients and acquired patient data and samples. HMM conceived and supervised the study and data interpretation. MRF interpreted the genetics data, developed the manuscript draft and generated the figures. MRF and HMM wrote the manuscript with critical review input from AS, TC, CMW, JSL and CH. All authors reviewed and approved the final manuscript.
Funding The national PCD Diagnostic Service is funded by NHS England. Research in Southampton is supported by NIHR Southampton Respiratory Biomedical Research Unit, NIHR Wellcome Trust Clinical Research Facility and the AAIR Charity (Reg No 1129698). Funding for this study was provided by Action Medical Research (GN2101; HMM) and Great Ormond Street Children’s Charity grant (V4515; HMM) and Leadership awards (V1299, V2217; HMM). We acknowledge support from the NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London (Doctoral Trainee Support Award; MRF). MRF is supported by the British Council Newton-Mosharafa Fund and the Ministry of Higher Education in Egypt. Work by AS is an independent research funded by a postdoctoral research fellowship from the National Institute for Health Research and Health Education England. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. The authors participate in and acknowledge financial support from the COST Action BEAT-PCD: Better Evidence to Advance Therapeutic options for PCD network (BM1407), in particular two STSM grants awarded to MRF.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval Patient recruitment took place with informed, age-appropriate consent as approved by the London-Bloomsbury Research Ethics Committee (08/H0713/82) and the committees of collaborating institutions.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. Data are available upon reasonable request.
Author note The authors are members of COST Action BEAT-PCD (BM1407).
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