Objective: To characterize GBA variants in a cohort of German patients with PD.

Background: GBA encodes the lysosomal enzyme beta-glucocerebrosidase A. GBA mutations cause the lysosomal storage disorder Gaucher disease (GD, types 1, 2, and 3) and have been found to increase the risk of Parkinson´s disease (PD), reduce age at PD onset and increase the risk of neuropsychiatric manifestations in PD. In fact, GBA mutations are the largest risk factor for idiopathic PD identified to date. Several genetic variants (polymorphisms), which do not cause GD, have also been found to be associated with an increased risk for PD. Heterozygous GBA mutation carriers have a risk of 10-30% to develop PD by age 80 years, corresponding to a 20-fold increase versus non-carriers; 5-25% of non-familial PD patients carry GBA mutations. GBA variants have further been shown to be associated with a distinct cognitive profile in PD (prevailing deficits in working memory, executive function and visuospatial abilities).

Method: Whole-gene sequencing of the GBA gene (11 exons; NP_000148.2) was performed using DNA samples of 332 German patients with PD (primer sequences available upon request). All patients were Caucasian; 32% had a positive family history.

Results: All 11 GBA exons were sequenced with 100% coverage. We found GBA variants in 44 out of 326 German patients (13.5%), including 13 non-synonymous (one of them being novel), three synonymous, and one nonsense variant (exon 8) as well as one deletion (exon 1). We present data including minor allele frequencies and in silico pathogenicity analyses for all variants identified. Six patients were heterozygous and two patients were homozygous for the E365K polymorphism. The N370S mutation was not found.

Conclusion: We report data on whole gene sequencing of the GBA gene in a large cohort of German patients. GBA variants were frequent in our cohort of German patient with PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/variants-in-the-beta-glucocerebrosidase-a-gba-gene-in-german-patients-with-parkinsons-disease/