Parkinson Disease and Complex Parkinsonism
Gene: GBAAdded 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
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
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
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
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.
Tag new-gene-name tag was added to gene: GBA.
Publications for gene: GBA were set to 27779773; 27632223; 27648471; 27717005; 29400127
Mode of inheritance for gene: GBA was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mode of inheritance for gene: GBA was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Gene: gba has been classified as Green List (High Evidence).
19th Dec 2016: panel revised according to expert review and further curation.
Publications for GBA were set to 27779773; 27632223; 27648471;27717005
This gene has been classified as Amber List (Moderate Evidence).
This gene has been classified as Red List (Low Evidence).
Publications for GBA were set to 27779773; 27632223; 27648471
This gene has been classified as Red List (Low Evidence).
Phenotypes for GBA were set to {Parkinson disease, late-onset, susceptibility to}, 168600
GBA was added to Parkinson Disease and Complex Parkinsonismpanel. Sources: Radboud University Medical Center, Nijmegen
GBA was created by ellenmcdonagh