LAUSR

Mutations that cause PCD have been reported in 50 genes. These account for around 70% of cases, with additional genes, and non-coding or synonymous changes in known genes, to be identified. Many adult patients with non-CF bronchiectasis have not been investigated for PCD. UK patients with no genetic confirmation for cause of PCD or bronchiectasis had whole genome testing in the UK 100,000 Genome Project (GP). Ciliopathies accounted for 1% of the rare disease cohort in the 100K GP. There were 143 PCD cases (34 probands) and 163 individuals with non-CF bronchiectasis (93 probands). 31% of PCD patients and 5% of bronchiectasis patients had biallelic pathogenic mutations in known PCD genes. We report on these genetically solved cases. In addition to these solved cases, we have identified 21 PCD patients (17%) and 31 non-CF bronchiectasis patients (22%) who have either one pathogenic variant or two variants of unknown significance (VUS) in relevant disease genes. We hypothesise that in patients with a single pathogenic variant identified, a second intronic or synonymous/non-synonymous deep exonic variant is affecting splicing, or that one or both VUS in patients will affect splicing. Using RNA analysis of ALI-cultured nasal ciliated epithelium, we demonstrate how we can uplift diagnostics in these cases (Figure Time course analysis of PCD gene expression during ALI-culture of respiratory epithelium using RNAseq).