Background
The p.A53T variant in the gene was considered, until recently, to be the only variant causing familial Parkinson's disease (PD) in the Greek population. We identified a novel heterozygous p.A30G (c.89 C>G) pathogenic variant in five affected individuals of three Greek families, leading to autosomal dominant PD. This study aims to further explore the presence and phenotypic expression of this variant in the Greek PD population.
Methods
Restriction fragment length polymorphism (RFLPs) was used for genotyping of 664 Greek PD cases. Detailed clinical information was obtained for the carriers and p.A30G‐positive samples underwent haplotype analysis.
Results
We identified 10 additional p.A30G‐positive PD patients (1.5%), of whom 4 were sporadic cases (0.9%). They manifested typical Parkinsonian motor dysfunction, with a mean age of onset of 51.7 years (range: 33–62) and a broad spectrum of non‐motor symptoms. The absence of affected first degree relatives in four out of ten index cases, and the presence of a phenocopy in an additional family, suggest that the p.A30G variant manifests reduced penetrance. The common haplotype among the p.A30G carriers confirmed a founder effect. Furthermore, two asymptomatic carriers were identified, with possible premotor manifestations.
Conclusions
These findings underscore that the p.A30G pathogenic variant represents an important, albeit rare, cause of genetic PD in the Greek population. This is the first time in which a genetic synucleinopathy, with a variant in the gene, is clearly linked to an appreciable frequency of sporadic PD in a particular population.