LRRK2 in Parkinson's disease - drawing the curtain of penetrance: a commentary

Abstract

Parkinson's disease is the most common neurodegenerative movement disorder and affects about 2% of the population over the age of 60 years. In 2004, mutations in the LRRK2 gene were first described and turned out to be the most frequent genetic cause of familial and sporadic Parkinson's disease and may account for up to 40% of patients in distinct populations. Based on these findings, Latourelle and colleagues show that the penetrance of the most common LRRK2 mutation is higher in patients with familial compared with sporadic Parkinson's disease and identified a substantial number of affected relatives of mutation carriers not presenting with a LRRK2 mutation themselves. This commentary discusses the role of genetic and/or environmental susceptibility factors modulating the expressivity of the disease trait, how these factors may contribute to the phenomenon of phenocopies in genetically defined Parkinson's disease pedigrees, and how the findings of Latourelle and colleagues, published this month in BMC Medicine, relate to current concepts of genetic counselling.

Figure 1

Schematic view of the variable penetrance of the different known mutant genes and genetic risk factors involved in familial and sporadic Parkinson's disease illustrating current hypotheses on the impact of genetic modifiers in expressivity of the disease. The higher the penetrance of a certain genetic trait, the more likely a familial clustering of the disease is observed, while lower penetrance is associated more with sporadic occurrence of Parkinson's disease. The G2019S mutation in the LRRK2 gene falls in the middle of this spectrum and may require the impact from additional susceptibility factors for full penetrance.