Submission Details

In 1987, biallelic GBA pathogenic variants were first linked to Gaucher's disease (Tsuji et al. 1987, PMID: 2880291), which is an autosomal recessive lysosomal storage disorder. However, it was noted that several of these probands with Gaucher's disease also had parkinsonian features and an unexpectedly high number of obligate (heterozygous) carrier relatives had Parkinson's disease. GBA was first systematically reported in relation to Parkinson's disease in 2004 (Aharon-Peretz et al. 2004, PMID: 15525722; Goker-Alpan et al. 2004, PMID: 15591280). Parkinson's disease is a progressive degenerative disorder of the central nervous system characterized by loss of dopamine producing neurons in the substantia nigra, and the presence of Lewy bodies in the substantia nigra and locus coeruleus in most cases. Signs and symptoms of Parkinson’s disease include tremor which is most pronounced during rest, muscle rigidity, slowing of the voluntary movements (bradykinesia), a tendency to fall back (postural instability). Different pathogenic GBA variants occur in 7–15% of PD patients (Blandini et al. 2019, PMID: 30589955; Sidranski et al. 2009, PMID: 19846850) and the PD risk increase is between 2- to 15-fold for carriers of GBA variants depending on the severity of the respective change (Gan-Or et al. 2015, PMID: 25653295). Thus, GBA-linked Parkinson's disease shows either a highly reduced penetrance or can be considered as a strong genetic risk factor. Several variants have been linked to Parkinson's disease, including those variants that in the biallelic stage have been shown to cause different forms of Gaucher's disease, seven of these variants (missense, frameshift, splice site, complex rearrangements) are included in this curation. The evidence for additional variants from the literature was not included in this curation because the maximum score for genetic evidence (12 pts.) has been reached. The GBA gene encodes the lysosomal enzyme beta-glucocerebrosidase (GCase) which catalyzes the hydrolysis of glucosylceramide (Glc-Cer) to ceramide and glucose. Reduced GCase activity has repeatedly been shown in mutant patient-derived and non-patient cells suggesting a loss-of-function mechanism (Alcalay et al. 2015, PMID: 26117366; Li et al. 2019, PMID: 30160596; Kim et al. 2021, PMID: 33753743). On the other hand, specific effects of mutant GBA protein on mitochondrial priming and autophagy induction indicate a gain-of-toxic-function (Li et al. 2019, PMID: 30160596). This effect may be attributed to the ER retention of mutant GBA, resulting in an unfolded protein response (Bendikov-Bar et al. 2011, PMID: 21106416). Furthermore, it has been repeatedly shown that mutant GBA promotes the accumulation of alpha-synuclein which is a pathological hallmark of Parkinson's disease (Schöndorf et al. 2014, PMID: 24905578). Following gene correction of the GBA mutations, the alpha-synuclein levels/accumulation were reduced to normal values (Schöndorf et al. 2014, PMID: 24905578). Notably, genomic multiplication (i.e. over-expression) of the alpha-synuclein gene (SNCA) is another well-established cause of Parkinson's disease. In summary, mutations in GBA are definitively causing autosomal-dominant Parkinson´s disease but with highly reduced penetrance. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Parkinson’s Disease Gene Curation Expert Panel on April 19th, 2022.