The application of next generation sequencing to identify mutations causing Parkinson’s disease and Parkinsonism

Abstract

Parkinson disease (PD) is the second most common neurodegenerative disorder characterized by muscle rigidity, bradykinesia and resting tremor, with a complex aetiology due to both genetic and environmental factors. Mode of inheritance can be either recessive or dominant, however, many of the cases are sporadic. Several genes have been implicated in PD, most importantly LRRK2, PINK, SNCA, PARK2, PARK7 and PARK5. Many mutations have been reported in these genes but very few have been confirmed to be solely the cause of disease. The identified mutations only explain the genetics of a small fraction of PD cases, suggesting that more mutations have yet to be identified. In this study, next generation sequencing (NGS) of the 6 main PD genes has been carried on 6 cases of PD/PS. LRRK2 NGS data from 15 healthy subjects was also available for analysis. Missense mutations were identified in LRRK2, PINK1 and PARK2. A novel mutation, LRRK2 c.A1853G:p.N618S, and the previously reported LRRK2 c.1550-9AG were selected for genotyping in the Maltese GeoParkinson collection, a case control collection consisting of 139 cases with PD/PS and 292 gender and frequency matched controls, collected as part of the EU funded FP5 GeoParkinson study. LRRK2 c.1550-9AG was found to be equally frequent in both cases and controls and therefore it was not found to be pathogenic. The LRRK2 c.A1853G:p.N618S was more frequent in cases (11.3%) than in controls (5.2%). Odds ratio calculations using logistic regression gave an OR of 2.32 (95%CI: 1.07-6.24; p=0.04) and thus p.N618S doubles risk for PD in the Maltese population.