Sinthuja PACHCHEK PEIRIS

Accurate long-read sequencing identified GBA variants as a major risk factor in the Luxembourgish
cohort


Objective: Assess the entire set of variants in the glucocerebrosidase (GBA) gene by long-read
sequencing in the Luxembourg Parkinson’s study (LuxPARK) and characterize genotype-phenotype
correlations of Parkinson’s disease (PD) patients carrying GBA variants.
Background: Heterozygous variants in the GBA gene are an important risk factor for PD. Because of
the pseudogene GBAP1 that shares 96% sequence homology with the coding region of the GBA,
accurate variant calling by array-based or short-read sequencing methods remains a major challenge
in understanding the genetic landscape of GBA related PD.
Methods: We used a long-read sequencing technology targeting the whole GBA gene developed by
Pacific BioScience (PacBio).
Results: We sequenced 792 cases and 807 healthy controls. All GBA variants called from PacBio HiFi
data could be validated with Sanger sequencing showing a true positive rate of 100%. 10.3% of PD
cases carried GBA variants, compared with 4.2% of controls. The low-risk variant, p.E365K, was the
most common variant among Luxembourgish PD patients. In addition, eleven variants of unknown
significance were identified. We confirm that the more severe the GBA variant, the more severely it
impacts the clinical effect.
Conclusions: For the first time, we demonstrated the high accuracy of GBA targeted PacBio
sequencing as a high specificity method to identify known and novel GBA variants. These findings
offer important access for GBA stratified therapies in the future. Furthermore, our study describes
the full landscape of GBA related PD in the current Luxembourg population showing the high
prevalence of GBA variants as the major genetic risk in PD.
Keywords: GBA, glucocerebrosidase, Parkinson’s disease, Genetics, long-read sequencing,
Luxembourg

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