Objective: Survival of patients with monogenic Parkinson's disease may depend on the causative genes associated with the disease. In this study, we compare survival of patients with Parkinson's disease according to the presence of SNCA, PRKN, LRRK2, or GBA mutations. Methods: Data from the French Parkinson Disease Genetics national multicenter cohort study were used. Patients with sporadic and familial Parkinson's disease were recruited between 1990 and 2021. Patients were genotyped for the presence of mutations in the SNCA, PRKN, LRRK2, or GBA genes. Vital status was collected from the National death register for participants born in France. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using multivariable Cox proportional hazards regression. Results: Of the 2,037 patients with Parkinson's disease, 889 had died after a follow-up of up to 30 years. Patients with PRKN (n = 100, HR = 0.41; p = 0.001) and LRRK2 mutations (n = 51, HR = 0.49; p = 0.023) had longer survival than those without any mutation, whereas patients with SNCA (n = 20, HR = 9.88; p < 0.001) or GBA mutations (n = 173, HR = 1.33; p = 0.048) had shorter survival. Interpretation: Survival differs across genetic forms of Parkinson's disease, with higher mortality for patients with SNCA or GBA mutations, and lower mortality for those with PRKN or LRRK2 mutations. Differences in severity and disease progression among monogenic forms of Parkinson's disease likely explain these findings, which has important consequences for genetic counselling and choice of end points for future clinical trials for targeted therapies.

BackgroundBackground: CAG-repeat expansions in Ataxin 2 (ATXN2) are known to cause spinocerebellar ataxia type 2 (SCA2), but CAA interrupted expansions may also result in autosomal dominant Parkinson's disease (AD PD). However, because of technical limitations, such expansions are not explored in whole exome sequencing (WES) data. Objectives Objectives: To identify ATXN2 expansions using WES data from PD cases. Methods Methods: We explored WES data from a cohort of 477 index cases with PD using ExpansionHunter (Illumina DRAGEN Bio-IT Platform, San Diego, CA). Putative expansions were confirmed by combining polymerase chain reaction and fragment length analysis followed by sub-cloning and sequencing methods. ResultsResults: Using ExpansionHunter, we identified three patients from two families with AD PD carrying either ATXN2 22/39 or 22/37 repeats, both interrupted by four CAA repeats. Conclusion Conclusion:These findings demonstrate the usefulness of WES to detect pathogenic CAG repeat expansions, which were found in 1.7% of AD PD in the ATXN2 gene in our exome dataset.Parkinson's disease (PD) is a neurodegenerative disorder characterized by a triad of symptoms: akinesia, rigidity, and rest tremor, and is associated with a good response to levodopa therapy. These symptoms are because of the degeneration of dopaminergic neurons of the substantia nigra secondary to the accumulation of aggregated α-synuclein. [1][2][3] Although the cause of PD is commonly sporadic, Mendelian forms account for 5% to 10% of cases. 4 Disease causing variants, mostly in SNCA, LRRK2, and VPS35 have been identified in patients with autosomal dominant (AD) PD. In addition, we and others have previously described families with heterozygous expansions in Ataxin 2 (ATXN2) presenting with predominant parkinsonian symptoms and in some cases with typical AD PD. [5][6][7][8][9][10][11] As in ataxic forms of spinocerebellar ataxia type 2 (SCA2), the expanded allele contained >33 repeats, but in PD, they were often interrupted by one or more CAA codons. 12 Next-generation sequencing (NGS) has proven to be of great diagnostic value in clinical practice, 13 but until recently, was thought to have a limited ability to assess for loci containing repeat expansions. Over the last few years, several bioinformatic tools for genome-wide genotyping of short tandem repeats (STRs) in short read sequencing data, mainly from whole genome sequencing (WGS) data have been developed. [14][15][16][17] However, despite the extensive application of whole exome