A systematic genomic screen of 755 early-onset Parkinson’s patients from the 100,000 Genomes Project increases diagnostic yield and directs clinical pathways

Parkinson’s Disease (PD) is a common neurodegenerative condition with a strong genetic aetiology, particularly in early-onset and familial cases. Nonetheless, only a handful of causal genes have been identified and genomic diagnostic yields remain low. This study investigates 755 early-onset and complex Parkinson’s cases from Genomics England. We describe existing diagnosed cases, in whom the yield was 5.2%, and assess coding and non-coding variation in undiagnosed cases to increase the yield to 11.3%. We demonstrate the utility of considering a wider diagnostic gene panel in individuals with complex presentation and provide support for genes that are emerging in the Parkinson’s literature ( ARSA , DNAJC13 , VPS13C , SPG7 and SQSTM1 ). We further illustrate how combined consideration of genotype and phenotype can help to stratify Parkinson’s cohorts. Despite this, 89% of our cohort remained undiagnosed underlining the importance of the continued identification of new genes that contribute to monogenic Parkinson’s.