Genome sequencing reveals underdiagnosis of primary ciliary dyskinesia in bronchiectasis.

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.

Multivesicular release at developing Schaffer collateral-CA1 synapses: an analytic approach to describe experimental data.

We developed and analytically solved a simple and general stochastic model to distinguish the univesicular from the multivesicular mode of glutamate release. The model solution gives analytical mathematical expressions for average values of quantities that can be measured experimentally. Comparison of these quantities with the experimental measures allows one to discriminate the release mode and to determine the most probable values of model parameters. The model has been validated at glutamatergic CA3-CA1 synapses in the hippocampus from newborn (P1-P5 old) rats. Our results strongly support a multivesicular type of release process requiring a variable pool of immediately releasable vesicles. Moreover, computing quantities that are functions of the model parameters, the mean amplitude of the synaptic response to the release of a single vesicle (q) was estimated to be 5-10 pA, in very good agreement with experimental findings. In addition a multivesicular type of release was supported by the following experimental evidences: 1) a high variability of the amplitude of successes, with a coefficient of variation ranging from 0.12 to 0.73; 2) an average potency ratio a2/a1 between the second and first response to a pair of stimuli >1; and 3) changes in the potency of the synaptic response to the first stimulus when the release probability was modified by increasing or decreasing the extracellular calcium concentration. Our results indicate that at Schaffer collateral-CA1 synapses of the neonatal rat hippocampus a single action potential may induce the release of more than one vesicle from the same release site.