Objective: We undertook mutation analysis of the Glucocerebrosidase gene (GBA) gene in a large three-generational Australian kindred consisting of some individuals with both type 1 Gaucher’s disease (GD) with and without Parkinson’s disease (PD) as well as others with PD alone.

Background: GBA mutations, initially recognised as the cause of GD, are now established as the most important genetic risk factor for developing PD. Lysosomal GBA enzymatic deficiency impairs α-synuclein clearance. Although more than 300 GBA mutations have been described, pathogenic mutations are most likely to be found in rare families with individuals manifesting both GD and PD. Heterozygous mutations in GBA may be present in 4-28% of patients with PD, with many patients manifesting symptoms in their forties, often clinically indistinguishable from sporadic PD aside from accelerated cognitive impairment.

Methods: A combination of whole exome sequencing and exon Sanger sequencing was used to validate novel variants and test for segregation in the family.

Results: A novel missense heterozygous mutation in the GBA gene, p.W378R in exon 9 was identified in the kindred segregated in five affected members: two individuals with a heterozygous W378R allele conferring PD risk; three had a compound heterozygous W378R/N370S alleles (two with PD-GD and one with only GD). Six of ten variant carriers developed PD, a penetrance of 60%. One elderly individual with a heterozygous W378R allele was asymptomatic but had mild extra-pyramidal features suggestive of PD.

Conclusions: We have identified a novel pathogenic variant in the GBA gene (W378R), which has a high penetrance and could confer both type 1 GD (when compound heterozygous with the common GD mutation N370S) and PD in the heterozygous state in six of ten variant carriers. These results show that the W378R mutation in GBA is likely to be a pathogenic allele contributing to GD and is a strong risk factor for PD. Early recognition of such PD-GBA mutations may enable timely access to new preventative therapies for PD, some of which have commenced therapeutic trials.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/novel-gba-risk-factor-gene-mutation-p-w378r-in-a-kindred-with-gauchers-disease-and-parkinsons-disease/