Parkinson Disease and Complex Parkinsonism

Gene: GBA

Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1.

Created: 30 Jun 2022, 3:17 p.m. | Last Modified: 30 Jun 2022, 4:13 p.m.

Panel Version: 1.108

Red List (low evidence)

Following a return of a GBA variant in the context of Parkinson disease by 100K, we feel that we need to feedback that this has posed issues after extensive MDT discussion:
Whilst we think the variant identified is pathogenic in the context of Gaucher's disease, and acknowledge that it could also be a risk factor for PD, we cannot further interpret it (ACMG guidelines are not suitable for risk alleles) so don't feel it's particularly clinically useful in the context of PD. However, we feel we have a responsibility to report in the context of Gaucher's disease carrier status for the benefit of other family members. We are concerned that when other family members request testing for the familial variant, which we would only interpret in the context of Gaucher's disease, they may mis-interpret this as a 'predictive' PD test (the index case was referred from neurology rather than clinical genetics) or worry about the associations of PD (but the majority of GD patients and heterozygote carriers do not develop PD PMID: 29385658).
Do the possible therapeutic benefits suggested for a small number of subclinical GD cases who also have PD outweigh these issues?

Created: 11 Sep 2019, 2:01 p.m. | Last Modified: 11 Sep 2019, 2:05 p.m.

Panel Version: 1.66

Publications

• 29385658

Green List (high evidence)

I think GBA1 variants should definitely be reported in neurological cases. GBA1 variants are reported as susceptibility factors but also in some dominant Parkinsons disease families. In a series I worked on about 5% of North London PD cases had a GBA1 variant.

in some case series people with PD have been found to have bi-allic GBA mutations (ie subclinical Gaucher), this clearly has therapeutic implications for them.

Created: 16 Apr 2018, 9:24 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Parkinsonism; Parkinsons disease

Publications

• https://www.ncbi.nlm.nih.gov/pubmed/29400127

Red List (low evidence)

Biallelic mutations in this gene cause Gaucher disease. Inheritance of a single mutation in GBA increases the risk for PD (Aharon-Peretz et al. 2004). In Ashkenazi Jewish the frequency of two common mutations in GBA (p.N370S and p.L444P) was 15 percent in PD and 3 percent in controls; whereas non-Ashkenazi Jewish populations demonstrated a much lower 3 percent frequency of these mutations in cases and < 1 percent in controls (Sidransky et al. 2009). Overall, these data indicate that a single-heterozygous mutation in GBA escalates the risk for PD around 5 fold, while remaining inadequate to cause Gaucher s disease. These two variants have also been linked to risk for dementia with Lewy bodies and PD with dementia (Nalls et al. 2013). Some variants accelerate cognitive decline in pd (27717005). DO not report back, as GBA is only a risk factor.

Created: 14 Dec 2016, 5:27 p.m.

Publications

• 27717005

Comment on list classification: Follow up from Alisdair McNeill's review: Promoted from Amber to Green after discussion with Arianna Tucci (internal Genomics England Clinical Team), who agrees that due to the view of the potential therapeutic implications it might be beneficial to have it as green. I have made the mode of inheritance both monoallelic and biallelic, to capture the patients who do have subclinical Gaucher disease.

Created: 13 Aug 2018, 4:21 p.m.

Comment on list classification: Biallelic mutations in this gene lead to Gaucher disease. Development of Parkinsons has been reported in several Gaucher disease cases. This is a PD susceptibility gene. Variants in this gene are associated with increased risk of dementia in PD patients, and a more rapid rate of cognitive decline (PMID: 27779773; 27632223). Unclear whether predictive testing could be used (PMID: 27779773). Mixed reports for association with different variants PMID: 27648471.

Created: 3 Nov 2016, 11:49 a.m.