S10 Whole genome analysis of familial pneumothorax by the 100,000 genomes project

BackgroundSpontaneous pneumothorax can be the presenting feature of several genetic disorders including Birt-Hogg-Dubé, Marfan, and vascular Ehlers-Danlos syndromes. Diagnosing these conditions enables personalised management that can prolong life for the probands and their relatives. At least 10% of individuals suffering an apparently primary spontaneous pneumothorax have an affected first or second-degree relative, and so should more accurately be labelled as having familial pneumothorax. Currently, assessment in our specialist pneumothorax clinic arrives at a diagnosis in only 20% of cases of familial pneumothorax. It is unclear if this reflects the failure to diagnose known syndromes or the existence of, as yet, undiscovered causes. The 100,000 Genomes Project recruited patients with a range of cancers or rare diseases, including familial pneumothorax.MethodThirty-two individuals with familial pneumothorax but no obvious syndromic cause were recruited. Whole genome sequencing was performed and potentially pathogenic variants were identified. Comparison was made with public databases, including Gnomad, and with a control cohort of recruits to the 100,000 Genomes Project with unrelated conditions. PanelApp, a crowdsourcing tool, was used to classify known pneumothorax-genes as ‘tier 1’ (clinically validated); plausible pneumothorax-genes as ‘tier 2’ (case report evidence), and all other genes as ‘tier 3’. Phenotypic information, from recruitment questionnaires, and past medical history, from NHS Hospital Episode Statistics, were also scrutinised.ResultsDespite efforts to exclude known pneumothorax syndromes, one recruited individual had a mutation in FLCN, a tier 1 gene causative of Birt-Hogg-Dubé syndrome. This suggests that most patients with known pneumothorax syndromes can be diagnosed by clinico-radiological assessment, though analysis for copy number and structural variants is ongoing. Our analysis identified few rare alleles to be shared by the remaining individuals. Far more often, a small group of common loss-of-function alleles was enriched in non-syndromic familial pneumothorax. Further work is ongoing to determine the genetic basis for those patients without a genetic diagnosis to date.ConclusionUsing whole genome sequencing we have demonstrated that clinico-radiological assessment identifies most individuals with currently known pneumothorax syndromes. Further work is ongoing to determine the genetic basis for those patients without a geneti