Genetic diagnosis of motile ciliopathies is conducted by healthcare, commercial and private laboratories. 88 genes have been implicated in motile ciliopathies (PCD, male infertility and associated disorders). Gene-disease relationships are uncertain where evidence is limited, risking inaccurate reporting and diagnosis. The ClinGen Motile Ciliopathy Gene Curation Expert Panel (GCEP) was set up collaboratively with BEAT-PCD ERS CRC in 2021. The GCEP comprises geneticists, pulmonologists and biocurators (Canada, France, Germany, Norway, Poland, Spain, Tunisia, UK, USA) tasked with classifying clinical validity of gene-disease relationships in motile ciliopathies to aid interpretation of genetic results. As an early step, the GCEP drew up guidelines to capture the critical details of motile ciliopathy cases and to score genetic and experimental evidence conservatively and consistently. The GCEP meets monthly and so far has curated 33 gene-disease relationships (https://clinicalgenome.org/affiliation/40102/). 22 curations have reached a definitive classification as the role of the gene in disease has been repeatedly demonstrated and upheld over time, 4 were disputed. These efforts provide a basis for future classifications of gene-disease relationships. The goal of the GCEP is to leverage emerging research to enhance the reliability of genetic testing for improved clinical detection and diagnosis of motile ciliopathies.
Background: Primary ciliary dyskinesia (PCD) represents a group of rare hereditary disorders characterized by deficient ciliary airway clearance that can be associated with laterality defects. We aimed to describe the underlying gene defects, geographical differences in genotypes and their relationship to diagnostic findings and clinical phenotypes. Methods: Genetic variants and clinical findings (age, sex, body mass index, laterality defects, FEV1) were collected from 19 countries using the ERN LUNG International PCD Registry. Genetic data were evaluated according to ACMG guidelines. We assessed regional distribution of implicated genes and genetic variants as well as genotype correlations with laterality defects and FEV1. Findings: 1,236 individuals carried 910 distinct pathogenic DNA-variants in 46 PCD genes. We found considerable variation in the distribution of PCD genotypes across countries due to the presence of distinct founder variants. The prevalence of PCD genotypes associated with pathognomonic ultrastructural defects (mean 72%; 47-100%) and laterality defects (mean 42%; 28-69%) varied widely among the countries. The prevalence of laterality defects was significantly lower in PCD individuals without pathognomonic ciliary ultrastructure defects (18%). The PCD cohort had a reduced median FEV1 z-score (-1·66). In the group of individuals with CCNO (-3·26), CCDC39 (-2·49), and CCDC40 (-2·96) variants, FEV1 z-scores were significantly lower, while the group of DNAH11 (-0·83) and ODAD1 (-0·85) variant individuals had significantly milder FEV1 z-score reductions compared to the whole PCD cohort. Interpretation: This unprecedented multinational dataset of DNA variants and information on their distribution across countries facilitates interpretation of genetic epidemiology of PCD and provides prediction of diagnostic and phenotypic features such as the course of lung function. Funding: Deutsche Forschungsgemeinschaft and Registry Warehouse (Germany).Declaration of Interest: I have no conflict of interest.
Background: The estimated prevalence of tracheobronchomalacia (TBM) in the general population is about 1:2100 and is reported to be increased in patients with cystic fibrosis. We could find no reports of TBM prevalence in primary ciliary dyskinesia (PCD). Aims: To study the prevalence of TBM in children with PCD aged <18 years. Methods: We performed a retrospective review of all children with confirmed or highly likely PCD at Oslo University Hospital undergoing transnasal flexible bronchoscopy (FB) between 2012–2019 for suspected TBM, atelectasis or diagnostic work-up, and who were assessed for TBM. TBM and lobar bronchomalacia (LBM) were defined as a subjective reduction of >50% in the airway cross-sectional area during quiet respiration or coughing. Results: We identified 22 (10F) patients, median (range) age 6.0 (0.4-15.3) yr who underwent FB; TBM was diagnosed in 7 (32%). 6 patients had LBM affecting at least one lobe, including 2 of 7 with TBM. In a further 8 patients with middle lobe atelectasis, LBM affecting the same lobe was present in 4. Excluding patients with atelectasis in whom LBM may be secondary, TBM or LBM was present in 10 (2:8, F:M) children (45%). One patient (no TBM/LBM) had chronic Pseudomonas Aeruginosa (PA) infection. Method: The high prevalence of TBM/LBM may partly be due to selection bias. Even allowing for bias, the prevalence was higher than expected and was not associated with chronic PA infection. These findings should be confirmed in larger studies.
We report three cases of vocal cord dysfunction (VCD) in adolescent boys. The aim of this article is to inform mental health professionals about VCD as a conversion phenomenon and its links with asthma. Suggested intervention needs to be pragmatic, based on explanation of symptom causation, practical strategies to avoid stridor and discussion with the family of the problems faced by the adolescents.
Background: Data on lung function in patients with PCD are few and contradictory. Within the EU project BESTCILIA, we compared lung function (FEV1) of patients with PCD to the Global lung function initiative (GLI) 2012 reference values and to published data from UK patients with Cystic Fibrosis (CF; Goss et al. Thorax 2015). Methods: We calculated z-scores and %predicted values for FEV1 using the GLI reference, and used a multilevel linear regression model, to account for repeated measurements, and adjusted for age, sex and study centre. Results: We obtained 4683 FEV1 measurements of 648 PCD patients from 15 centres. The median age was 16 years (range 6-70), 295 (46%) were females. In the multilevel model FEV1 z-scores (95% CI) were significantly lower than GLI values (FEV1 -1.5 (-1.6 to -1.4); p<0.005)). Both sexes and all age groups were affected, with a smaller difference for children aged <10 years (FEV1 z score -1.18 (-1.3 to -1.05). Compared to published data for CF, FEV1 %predicted (95% CI) was similar in children (e.g. age 6-9: PCD: 87% (86 - 89%); CF: 90% (88 - 91%)); but better in adult PCD patients (age 18-21: PCD: 76% (73 - 80%); CF: 66% (65 - 68%)). Conclusions: This is the largest study ever conducted on spirometry in patients with PCD. FEV1 was significantly reduced compared to normal reference values for all age groups and both sexes. Young children with PCD and CF both had a low FEV1, which later in life remained relatively stable in PCD unlike in CF. In the ongoing study, we will analyse determinants of lung function, particularly age at diagnosis, time since diagnosis, and diagnostic certainty. Funding: FP7 grant 305404, SNF32003B-144068.
Background: Ear problems are common in primary ciliary dyskinesia (PCD), but little is known on their spectrum and severity. We aimed to characterize otologic disease in PCD patients using data from the ENT Prospective International Cohort of PCD patients (EPIC-PCD), a multicentre prospective observational clinical cohort. Methods: We prospectively included patients with a routine ENT examination and a completed FOLLOW-PCD symptoms questionnaire at the same visit. We compared reported symptoms and clinical findings between children and adults. Results: We included 208 patients (108 males) with median age 16 years (range 0-63). 114 (55%) reported ear pain, 61 (29%) ear discharge and 105 (50%) hearing problems. Reported symptoms did not differ by age. On examination 20/179 (11%) patients had tympanic perforation, 28/174 (16%) retracted membrane and 52/175 (30%) otitis media with effusion (OME). Tympanic sclerosis was found in 41/165 (25%) patients and 18 patients had grommets. OME was more common in children and sclerosis in adults. 68 out of 101 patients had an abnormal tympanogram. Audiometry was performed in 131 patients, showing hearing loss in 63 (48%), usually mild and bilateral. 2 adults had severe hearing loss. Reported hearing problems and audiometry results were discordant in 22 patients; 15 reported normal hearing with abnormal audiogram while 7 patients reported hearing problems with a normal audiogram. Conclusion: This is the largest study describing otologic disease in PCD. Ear problems were common in patients of all ages although hearing loss was not perceived by some patients. This emphasizes the need for standardised ENT follow-up for all PCD patients. Funding: SNF PZ00P3_185923
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