Abstract
Background Bronchiectasis can result from infectious, genetic, immunological and allergic causes. 60–80% of cases are idiopathic, but a well-recognised genetic cause is the motile ciliopathy, primary ciliary dyskinesia (PCD). Diagnosis of PCD has management implications including addressing comorbidities, implementing genetic and fertility counselling and future access to PCD-specific treatments. Diagnostic testing can be complex; however, PCD genetic testing is moving rapidly from research into clinical diagnostics and would confirm the cause of bronchiectasis.
Methods This observational study used genetic data from severe bronchiectasis patients recruited to the UK 100,000 Genomes Project and patients referred for gene panel testing within a tertiary respiratory hospital. Patients referred for genetic testing due to clinical suspicion of PCD were excluded from both analyses. Data were accessed from the British Thoracic Society audit, to investigate whether motile ciliopathies are underdiagnosed in people with bronchiectasis in the UK.
Results Pathogenic or likely pathogenic variants were identified in motile ciliopathy genes in 17 (12%) out of 142 individuals by whole-genome sequencing. Similarly, in a single centre with access to pathological diagnostic facilities, 5–10% of patients received a PCD diagnosis by gene panel, often linked to normal/inconclusive nasal nitric oxide and cilia functional test results. In 4898 audited patients with bronchiectasis, <2% were tested for PCD and <1% received genetic testing.
Conclusions PCD is underdiagnosed as a cause of bronchiectasis. Increased uptake of genetic testing may help to identify bronchiectasis due to motile ciliopathies and ensure appropriate management.
Abstract
Primary ciliary dyskinesia is underdiagnosed as a cause of idiopathic bronchiectasis. Whole-genome sequencing reveals variants in motile ciliopathy genes. https://bit.ly/3yKoBko
Introduction
Bronchiectasis is both a clinical disease and a radiological appearance that has multiple causes and can be associated with a range of conditions [1]. It can result from infectious, genetic, immunological or allergic causes, but the majority of cases are of unknown cause and termed “idiopathic” [2]. Guidelines recommend investigation of aetiology, since it can alter management [3, 4]. A targeted approach to aetiology can reduce the number of idiopathic cases reported [5]. Genetic causes include rare cystic fibrosis transmembrane receptor (CFTR) genotypes, channelopathies, immunodeficiencies and primary ciliary dyskinesia (PCD) [2]. The estimated PCD prevalence among adults with bronchiectasis is 1–13% [6–11]. Testing for PCD is suggested in patients with supporting clinical features, including a history of neonatal distress, symptoms from childhood, recurrent otitis media, rhinosinusitis or infertility [3]. Patients with adult-onset bronchiectasis arising from PCD are described as younger than their idiopathic bronchiectasis counterparts, having moderate impairment of lung function and higher rates of chronic infection with Pseudomonas aeruginosa [11–13]. Due to these risk factors and the multisystemic nature of PCD, in the UK, diagnosed PCD patients have access to a specific and multidisciplinary team approach to management in specialist PCD referral centres. Recently, the first randomised controlled trial for evidence-based medicine in PCD was completed, and specific therapies which target genetic defects are in development [12, 13]. Therefore, diagnosis is becoming increasingly important, as it impacts on clinical care.
Mutations in >50 different genes cause PCD and its spectrum of associated motile ciliopathies [14]. Diagnosing PCD is complex due to the requirement for a multitest approach requiring specialist expertise and equipment [15–17]. Therefore, the risk of late or missed diagnosis is high. Late diagnosis is associated with poorer prognosis [18]. In England, PCD testing is available at three specialist centres and includes evaluation by nasal nitric oxide (NO) measurement, high-speed video microscopy (HSVM), immunofluorescence, tissue culture at the air–liquid interface and transmission electron microscopy (TEM) [15, 19]. Genetic testing for PCD has now moved from a research-based test into clinical practice [14].
In this study we investigated the contribution of primary motile ciliopathies in bronchiectasis using three datasets: whole-genome sequencing (WGS) of patients recruited to the UK 100,000 Genomes Project, clinical gene panel sequencing of patients within a large tertiary PCD and bronchiectasis centre and PCD diagnostic data from the British Thoracic Society national audit. Specifically, the aim was to identify motile ciliopathies in patients in whom diagnosis was not strongly suspected. Our analysis demonstrates that despite comprehensive national PCD testing facilities, motile ciliopathies remain underdiagnosed in people with idiopathic bronchiectasis.
Methods
The 100,000 genomes project
The UK 100,000 Genomes Project, overseen by Genomics England (www.genomicsengland.co.uk), was initiated in 2013 to sequence 100 000 genomes from National Health Service (NHS) patients and their family members in the UK affected by rare diseases or cancer [20].
142 people were recruited as “non-cystic fibrosis (CF) bronchiectasis” (with 107 additional family members in a total cohort of 249 individuals). All participants provided written informed consent. Inclusion criteria were severe disease (forced expiratory volume in 1 s <30% predicted), or individual aged <50 years with involvement of more than one lobe or suspicion of an inherited cause (including ciliopathies); full recruitment inclusion/exclusion criteria are shown in the supplementary material. Importantly, participants with strong clinical suspicion of PCD were recruited to the 100,000 Genomes Project as a separate group and were excluded from the present study [21].
WGS was carried out using Illumina short-read sequencing. Genomics England developed standardised data analysis pipelines (detailed in the supplementary methods) to filter and tier variants most likely to be clinically relevant.
We carried out expert curation of all variants tiered by Genomics England in non-CF bronchiectasis patients and applied additional complementary variant analysis pipelines. These interrogated an expanded panel of 91 genes associated with motile ciliopathies (supplementary table E3) for exonic or splice donor/acceptor single nucleotide, short insertion/deletion, copy number and structural variants that were predicted to be protein altering. Recently developed variant annotation tools (SpliceAI [22], UTRannotator [23]), were also applied to screen for additional, potentially protein-altering variants. Pathogenic and likely pathogenic variants in known disease genes for motile ciliopathies were categorised using the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) guidelines [24]. A summary of methodology and participant numbers can be found in supplementary figure E1.
Here we report individuals with genetic variants associated with motile ciliopathies only; other potentially disease-causing variants identified, for example those in CFTR, will be reported elsewhere.
Royal Brompton Hospital clinical genetics and genomics laboratory bronchiectasis panel audit results
In 2017, the Royal Brompton Hospital (London, UK) set up clinical genetic diagnostic testing for patients with respiratory disease, including targeted analysis of genes for bronchiectasis and PCD, as part of a custom “RespiGene” gene panel (Agilent Technologies). Sequencing was performed on an Illumina NextSeq550, and reads were mapped to human genome reference (GRCh38). Variants were classified for pathogenicity according to ACMG/AMP guidelines [24]. An in-house copy number variant caller was used and all likely pathogenic and pathogenic single nucleotide variants and copy number variants were confirmed by Sanger sequencing or digital droplet (dd)PCR, respectively. The 52-gene bronchiectasis panel consisted of CFTR, SCNN1A, B, D and G genes and 47 PCD genes (supplementary tables E2 and E3).
Results of all clinical referrals for the bronchiectasis panel between 2017 and 2020 were included. Patients with a strong clinical diagnosis of PCD were referred only for testing of a PCD gene subpanel and were excluded from this study. PCD diagnostic investigations (nasal NO, high-speed video microscopy, immunofluorescence and TEM) were performed as described previously [25–27].
British Thoracic Society audit
The 2017 British Thoracic Society (BTS) bronchiectasis audit was carried out across 105 hospitals with 4845 records. The audit focused on diagnosis and management of adult bronchiectasis. Audits applied to patients who had a follow-up or review outpatient appointment for bronchiectasis between 1 October and 30 November 2017. Data were collected from patient notes. Participants were asked to enter all eligible cases, or where this was not possible due to large numbers, to take care to avoid bias in case selection [28]. For the purpose of this analysis, cases in which the answer was yes to two or more of the following questions were considered to have severe disease: “advanced disease/considering transplantation”, “recurrent exacerbations (more than three per year)”; “deteriorating bronchiectasis with declining lung function”, “Pseudomonas isolated two or more times in the past 12 months”.
Results
WGS of patients with severe and familial bronchiectasis reveals mutations in genes associated with motile ciliopathies
17 (12%) out of 142 individuals with a clinical diagnosis of bronchiectasis screened by WGS as part of the 100,000 Genomes Project had pathogenic or likely pathogenic variants in a motile ciliopathy gene as listed in supplementary tables E2 and E3. Results for these individuals are shown in table 1. The mean age of those with bronchiectasis with variants suggestive of an inherited motile ciliopathy was 45 years, median (range) age 46.5 (21–75) years. The male:female ratio was 6:11, in keeping with a female predominance in patients with bronchiectasis [39]. These 17 patients were recruited across seven genomic medicine centres, including the three associated with specialist PCD diagnostic centres.
Genotypes of people recruited to the UK 100,000 Genomes Project as non-cystic fibrosis bronchiectasis carrying variants suggestive of primary ciliary dyskinesia
Two patients from consanguineous families were found to be homozygous for the relevant pathogenic variants. All other families were not knowingly consanguineous, and all patients had compound heterozygous variants except for one homozygous and two hemizygous X-linked patients. All individuals with causal variants in motile ciliopathy genes were reported to have sinusitis and recurrent respiratory infections. Where distribution of bronchiectasis was noted (10 cases), this was generally bilateral (nine out of 10). Where age of onset had been recorded (five cases), this was always childhood onset (five out of five). Three patients had dextrocardia, two had hydrocephalus, two had hearing impairment and one had bilateral otitis media.
Mutations in 13 different motile ciliopathy genes were recorded among the affected individuals from this cohort (table 1). Genetic diagnoses included 10 cases with pathogenic or likely pathogenic variants (also, three variants of unknown significance (VUS)) identified in several known PCD genes: CCDC39 (two cases), DNAI1 (two cases), DNAI2, DNAH5 (two cases), DNAH11, RSPH1 and RSPH4A. Two cases shared the same single de novo dominant FOXJ1 variant initially classified as a tier 3 VUS, until FOXJ1 was subsequently confirmed as a novel PCD gene associated with dominant inheritance through the identification of additional patients and further experimental analysis described elsewhere [35]. Two other affected individuals carried likely diagnostic X-linked PCD-causing variants in genes associated with additional clinical phenotypes [40, 41]: 1) an OFD1 variant c.3G>A identified as likely to affect the start codon and protein translation; however, this remains a tier 3 VUS without further experimental evidence, since the parental genotypes were not available to confirm familial segregation, and since PCD-linked OFD1 mutations tend to be located towards the 3′ end of the gene [42]; and 2) an RPGR variant c.602A>G creating a predicted missense amino acid substitution that also remains a VUS without experimental validation or parental genotypes available. Finally, autosomal recessive variants classified as pathogenic or likely pathogenic were also identified in CEP164, CFAP53 and NEK10 in three affected individuals. All three genes have previously been connected to motile ciliopathy phenotypes, with NEK10 and CEP164 mutations directly linked to causing bronchiectasis in humans [43–45]. CFAP53 mutations were previously associated with situs inversus, but only mild respiratory symptoms (recurrent cough, sinusitis) [46, 47].
Additional detailed analyses identified nine more cases with variants in ciliary genes, but of less-certain significance (supplementary table E5).
Of note, mutations in six of the 13 reported genes in table 1 are associated with nonclassical PCD clinical diagnostic findings of normal TEM and/or normal NO (FOXJ1, NEK10, OFD1, RPGR, DNAH11 and RSPH1). Nasal NO and nasal brushing data were not available for the 100,000 Genome cohort, and therefore we sought to replicate the findings through audit of genetic testing in bronchiectasis patients in a tertiary respiratory hospital.
Gene panel testing of bronchiectasis patients referred to a tertiary-care centre reveals mutations in genes associated with motile ciliopathies
56 patients with idiopathic bronchiectasis were referred to the Royal Brompton Hospital for diagnostic genetic testing (cases referred specifically for PCD genetic testing were excluded from this study). Four (7%) received a definite PCD genetic diagnosis, with two pathogenic or likely pathogenic variants identified in known PCD genes (CCDC103, CCDC40, DNAH11) (table 2). There were a further three potential diagnoses; two with a likely pathogenic variant plus a second variant in the same gene classified as a VUS (DNAH11, GAS2L2), and one apparently homozygous for an exon duplication (DNAL1). This increases the total number of cases in which biallelic mutations were identified to 12.5%, similar to the frequency of PCD gene variants seen in the 100,000 Genomes patient cohort. In a further four patients, a single heterozygous pathogenic/likely pathogenic variant was identified, but no second variant, precluding definitive diagnosis.
Genotypes of people referred with non-cystic fibrosis bronchiectasis to the Royal Brompton Hospital carrying variants suggestive of primary ciliary dyskinesia
33 out of 56 patients had cilia function tests prior to referral for genotyping. Two out of the four definite genetic PCD diagnoses had normal nasal NO (>77 nL·min−1). Normal functional tests associated with CCDC103 p.(His154Pro) variants are in keeping with previous descriptions [51]. Another patient was homozygous for a variant in CCDC40 (c. 940–1G>C) affecting an essential splice acceptor site. CCDC40 causal variants normally confer microtubular disorganisation and absent inner dynein arms (absence in immunofluorescence of GAS8 and DNALI1) [52, 53]. However, this complex case had unusual HSVM, TEM and immunofluorescence with some features not being the classical phenotype, as there was microtubular disorganisation and absent GAS8 but with the inner arms present when tested by TEM and immunofluorescence [52]. Furthermore, the individual has a brother who is a heterozygous carrier of the CCDC40 splice variant, who does not have respiratory symptoms, but has dextrocardia. These results make interpretation of the variant difficult; however, as demonstrated by phenotypes of patients carrying the missense CCDC103 H154P variant compared to those with a loss of function mutation in CCDC103, different mutations in the same gene do not always present functional cilia defects in the same way.
Functional analyses were also available on six out of seven individuals with a potential PCD genetic diagnosis. One case with a single likely pathogenic DNAH11 variant, c.3020T>G, and no second pathogenic allele had a typical HSVM pattern for DNAH11 defects, making the diagnosis highly likely. Another case with a single frameshift deletion of DNAAF1 (exon 2–3) and no second allele had atypical findings on HSVM for a DNAAF1 defect. Strikingly, this was the only individual in this cohort with low nasal NO.
BTS bronchiectasis audit data suggest that access to testing in the UK may limit diagnosis
4898 adults with bronchiectasis from 89 centres were included in the BTS audit. Only 95 (1.9%) were tested for PCD. 47 underwent nasal NO measurement, 45 TEM and 45 HSVM. 23 patients had nasal NO only, which is known to be normal in several motile ciliopathies. Evaluation by all three tests, as would be appropriate according to the European Respiratory Society guidelines [15], was performed in 22 (0.4%) patients. 597 people had a severe disease phenotype. Testing was more likely in this group and conducted in 15 (2.5%) people, of whom six (1%) received full testing. Given that the 100,000 Genome Project recruitment criteria included a category for age <50 years and PCD patients tend to be younger than their idiopathic counterparts, we analysed the data according to age. 56 (11%) out of those 534 aged <50 years were referred for testing and 12 (2%) out of 534 received full testing. These findings, taken together with the results of the 100,000 Genomes Project, suggest that there is insufficient testing for PCD in patients with bronchiectasis to identify the majority of affected patients.
Discussion
This multicentre study is one of the first to analyse WGS in bronchiectasis. Our study highlights underdiagnosis of PCD. We identified motile ciliopathy associated genes in 12% of idiopathic bronchiectasis patients recruited for WGS due to severe, familial disease or age <50 years.
The WGS project had the option to recruit patients under a PCD phenotype category; this infers that clinicians recruiting to the non-CF bronchiectasis category had not clinically diagnosed PCD in their patients, but did have suspicion of an inherited cause. Hence this level of diagnosis in a large portion of people recruited as non-CF bronchiectasis suggests that either there are barriers to accessing PCD testing and/or clinicians struggle to ascertain which cases have features suggestive of PCD. We have to question whether these truly are all cases where PCD should not have been suspected, given for instance that three had dextrocardia, upper airway symptoms and bronchiectaisis.
To identify if access to PCD testing was a barrier to diagnosis, we audited data from the specialist respiratory genetics service at the Royal Brompton Hospital which runs alongside a PCD diagnostic service. This identified that 7% patients referred for genetic testing with a clinical diagnosis of idiopathic bronchiectasis had pathogenic mutations in motile ciliopathy genes. Including those with a single pathogenic mutation with an abnormal functional test and/or variant of unknown significance, this rises to 12.5%. An additional 7% were found to be heterozygous for a single pathogenic variant in a known PCD gene. This could represent genuine PCD gene mutation carriers, found to be at more risk of bronchiectasis, or, alternatively, these may simply be cases where a second pathogenic variant was not identified by the current analysis. Typically, the gene panel-based genetic diagnosis of PCD is based upon a sequencing strategy that covers only the coding regions, the canonical splice sites and immediate flanking intronic sequence of the known genes; hence, it is postulated that in at least some of these patients, the second pathogenic variant may be in the noncoding regions of the relevant genes. There may also be more complex structural variants missed by the current computational analyses. Future work to achieve a higher diagnostic rate for bronchiectasis in this cohort could probably benefit from a more detailed interrogation of promoter and intronic regions of the relevant genes, not studied here, as well as further functional experiments to determine whether some of the variants identified in this study can provide a likely diagnosis.
Many of the patients with bronchiectasis in the Royal Brompton Hospital analysis were referred for PCD testing before genotyping, but the functional testing had given equivocal results. Normal nasal NO and normal TEM were present in most cases where tested. Normal NO and TEM have been described previously in some of the genes reported [34, 43, 49, 51, 54]. Importantly, our data suggest that nasal NO testing alone is not sufficient to exclude a diagnosis of PCD in bronchiectasis [55]. We suggest that NO is not a screening test and should be used as part of a diagnostic testing algorithm alongside other testing modalities such as genetics and nasal brushing.
Among the WGS and gene panel genetic diagnoses, several affected individuals carried causal variants in PCD genes that confer classic cilia structure and function defects. However, a number also carried variants in PCD genes linked to less classic defects (FOXJ1, OFD1, RPGR, RSPH1, CCDC103, GAS2L2). In three such cases (two also reported elsewhere [56]), variants were revealed in CEP164, CFAP53 and NEK10, genes currently linked to motile ciliopathy rather than clinically defined PCD. Previously, bronchiectasis in addition to syndromic features but no cilia functional testing was reported for CEP164 mutation patients; NEK10 was reported to cause bronchiectasis in patients with normal nasal NO levels, normal nasal ciliary ultrastructure and negligible ciliary beating abnormalities; and CFAP53 mutation patients also had normal NO and negligible reduction in airway ciliary beat frequency [43, 44, 46]. Patients with these milder respiratory features could therefore escape detection during standard PCD clinical evaluation.
Both the pre-defined cohorts (100,000 Genomes and Royal Brompton Hospital) were biased towards selection of more severe and familial disease and the prevalence in an unselected cohort may be less. A future unbiased study of all cases of bronchiectasis will define the rate of PCD in an unselected cohort. There is possible greater genetic heterogeneity than has been considered. In bronchiectasis, our cases of incomplete diagnoses imply that particular attention to sequencing of nonclassical PCD genes and ciliary gene variants located outside of exonic coding regions, with potentially less clear-cut effects on cilia motility, may be warranted. Both WGS and gene panel testing were successful at identifying undiagnosed motile ciliopathies. Using a panel of known PCD genes may be a cost-effective first step for referring patients with features of a motile ciliopathy, severe or familial bronchiectasis. Our data showing a significant contribution of ciliopathies within bronchiectasis cohorts support the need for a change in policy for genetic testing in bronchiectasis, as is now reflected in the National Genomic Test Directory guidelines for the UK NHS Genomic Medicine Service which includes the clinical indication “Respiratory ciliopathies including non-CF bronchiectasis”.
The BTS audit data shows that only 0.4% of people with bronchiectasis in the UK have guideline-recommended testing for PCD, despite the presence of a network of three specialist diagnostic services [57]. Better access will not resolve all the issues: the genetic cause is not identified in up to 30% of well-defined PCD patients; therefore, this may be an underestimate of the true prevalence of motile ciliopathy defects in a bronchiectasis cohort, and the true number of ciliopathy cases could account for up to 16% of the cohort [58–60].
We conclude that PCD is an underdiagnosed cause of severe adult bronchiectasis and that people with bronchiectasis who are young or have severe or familial disease should be tested for motile ciliopathies.
Supplementary material
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Acknowledgements
Study authors participate in the Bronch UK Consortium (www.bronch.ac.uk) who developed the inclusion groups within bronchiectasis for the 100,000 Genomes Project. Study authors and data contributors participate in the BEAT-PCD clinical research collaboration, supported by the European Respiratory Society. We acknowledge the BEAT-PCD Workpackage 2 team, for gene list input (WP2 Leads, Marie Legendre, Sorbonne Université, Paris, France and Suzanne Crowley, Oslo University Hospital, Oslo, Norway). Study authors participate in the EMBARC clinical research collaboration supported by the European Respiratory Society. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. The British Thoracic Society Audit 2017 data was provided by the British Thoracic Society (BTS). The contribution of all centres contributing to the BTS audit is gratefully acknowledged. This publication makes use of data provided by the British Thoracic Society Clinical Audit Programme which has no responsibility or liability for the accuracy, currency or correctness of this publication.
Footnotes
The Genomics England Research Consortium: D. Brown, J.C. Ambrose, P. Arumugam, R. Bevers, M. Bleda, F. Boardman-Pretty, C.R. Boustred, H. Brittain, M.J. Caulfield, G.C. Chan, T. Fowler, A. Giess, A. Hamblin, S. Henderson, T.J.P. Hubbard, R. Jackson, L.J. Jones, D. Kasperaviciute, M. Kayikci, A. Kousathanas, L. Lahnstein, S.E.A. Leigh, I.U.S. Leong, F.J. Lopez, F. Maleady-Crowe, M. McEntagart, F. Minneci, L. Moutsianas, M. Mueller, N. Murugaesu, A.C. Need, P. O'Donovan, C.A. Odhams, C. Patch, D. Perez-Gil, M.B. Pereira, J. Pullinger, T. Rahim, A. Rendon, T. Rogers, K. Savage, K. Sawant, R.H. Scott, A. Siddiq, A. Sieghart, S.C. Smith, A. Sosinsky, A. Stuckey, M. Tanguy, A.L. Taylor Tavares, E.R.A. Thomas, S.R. Thompson, A. Tucci, M.J. Welland, E. Williams, K. Witkowska, S.M. Wood.
Author contributions: Study conception and design: A. Shoemark, H. Griffin, G. Wheway, C. Hogg, J.S. Lucas, J.D. Chalmers, D. Morris-Rosendahl, H.M. Mitchison and A. De Soyza. Data collection: A. Shoemark, C. Hogg, J.S. Lucas, M. Carroll, M.R. Loebinger, D. Morris-Rosendahl and A. De Soyza. Data analysis: A. Shoemark, H. Griffin, G. Wheway, C. Camps, J.D. Chalmers, D. Morris-Rosendahl and H.M. Mitchison. Writing of the manuscript: A. Shoemark, H. Griffin, G. Wheway, C. Hogg, J.S. Lucas, J.D. Chalmers, D. Morris-Rosendahl, H.M. Mitchison and A. De Soyza. Revising critically for important intellectual content and final approval: all authors.
Conflict of interest: A. Shoemark has received grants from AstraZeneca. G. Wheway is currently employed by Illumina Inc. M.R. Loebinger has received consultancy or speaker fees from Insmed, AstraZeneca, Parion, Grifols and Armata. J.D. Chalmers has received grants or contracts from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Novartis and Insmed; and received consultancy or speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis and Zambon. J.S. Lucas reports grants from NHS England, NIHR and AIR Charity. H.M. Mitchison is a Trustee of Ciliopathy Alliance. A. De Soyza reports grants from AstraZeneca, GlaxoSmithKline and Pfizer; consulting fees and lecture honoraria from Gilead, GlaxoSmithKline, AstraZeneca, LifeArc and 30T; participation on advisory board at Bayer; receipt of equipment from GlaxoSmithKline. All other authors have nothing to disclose.
Support statement: H.M. Mitchison acknowledges funding from the NIHR Biomedical Research Centre at Great Ormond Street Hospital and the Ministry of Higher Education in Egypt. The National PCD Service is commissioned and funded by NHS England; PCD research in Southampton is supported by NIHR Southampton Biomedical Research Centre, NIHR Clinical Research Facility, National Institute for Health Research (RfPB PB-PG-1215-20014; and 200470) and The AAIR Charity (registration number 1129698).
- Received January 25, 2022.
- Accepted May 12, 2022.
- Copyright ©The authors 2022. For reproduction rights and permissions contact permissions{at}ersnet.org
References
