Genetics of Parkinson's Disease: Genotype-Phenotype Correlations

Since the first discovery of a specific genetic defect in the SNCA gene, encoding for alpha-synuclein, as a causative factor for Parkinson's disease 20 years ago, a multitude of other genes have been linked to this disease in rare cases with Mendelian inheritance. Furthermore, the genetic contribution to the much more common sporadic disease has been demonstrated through case control association studies and, more recently, genome-wide association studies. Interestingly, some of the genes with Mendelian inheritance, such as SNCA, are also relevant to the sporadic disease, suggesting common pathogenetic mechanisms. In this review, we place an emphasis on Mendelian forms, and in particular genetic defects which present predominantly with Parkinsonism. We provide details into the particular phenotypes associated with each genetic defect, with a particular emphasis on nonmotor symptoms. For genetic defects for whom a sufficient number of patients has been assessed, there are evident genotype-phenotype correlations. However, it should be noted that patients with the same causative mutation may present with distinctly divergent phenotypes. This phenotypic variability may be due to genetic, epigenetic or environmental factors. From a clinical and genetic point of view, it will be especially interesting in the future to identify genetic factors that modify disease penetrance, the age of onset or other specific phenotypic features.