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Parkinson Disease and Complex Parkinsonism v1.128 ARSA Ida Ertmanska changed review comment from: PMID: 37381728 Senkevich et al., 2023
Authors performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by meta-analysis, and found evidence for associations between rare functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each). Of note: "results should be interpreted with caution as no association survived multiple comparisons correction."

Authors also found potential co-segregation of p.E382K variant in two unrelated PD patients with history of MLD and PD. The variant was not found in any controls.
Family A, patient II-4 - 62yo, had Parkinson's disease, het for p.E382K; also a carrier of the GBA1 variant RecNcil - hence, impossible to estimate the role of the ARSA variant in PD.
Family A, individual IV-1 - 12yo, diagnosed with MLD, comp het for ARSA variants p.E382K and c.465G>T, p.Q155H.
Caveat: variant p.E382K = c.1150G>A, p.Glu384Lys (p.E384K) - MAF = 0.00005331 in gnomAD v4.1.1., no homozygotes. P/LP classification in ClinVar.
Family B: 5 family members with Parkinson's disease, 4 deceased and not genotyped (77-82yrs), individual II-4 (72yo) had PD and was ARSA wt/wt. Individual IV-1: 7yo, MLD diagnosis, comp het for ARSA variants p.E382K and c.1107+1G>A. Other het p.E382K carriers are aged under 60yo so not known if they will be affected by PD.

p.L300V variant found in two cases and one controls

PMID: 31312839 Lee et al., 2019
"ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein."; to: PMID: 37381728 Senkevich et al., 2023
Authors performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by meta-analysis, and found evidence for associations between rare functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each). Of note: "results should be interpreted with caution as no association survived multiple comparisons correction."

Authors also found potential co-segregation of p.E382K variant in two unrelated PD patients with history of MLD and PD. The variant was not found in any controls.
Family A, patient II-4 - 62yo, had Parkinson's disease, het for p.E382K; also a carrier of the GBA1 variant RecNcil - hence, impossible to estimate the role of the ARSA variant in PD.
Family A, individual IV-1 - 12yo, diagnosed with MLD, comp het for ARSA variants p.E382K and c.465G>T, p.Q155H.
Caveat: variant p.E382K = c.1150G>A, p.Glu384Lys (p.E384K) - MAF = 0.00005331 in gnomAD v4.1.1., no homozygotes. P/LP classification in ClinVar.
Family B: 5 family members with Parkinson's disease, 4 deceased and not genotyped (77-82yrs), individual II-4 (72yo) had PD and was ARSA wt/wt. Individual IV-1: 7yo, MLD diagnosis, comp het for ARSA variants p.E382K and c.1107+1G>A. Other het p.E382K carriers are aged under 60yo so not known if they will be affected by PD.

PMID: 31312839 Lee et al., 2019
Reported a 32yo female proband with MLD, comp het for ARSA variants p.L300S and p.C174Y. Her father and paternal uncle had Parkinson's disease, and were heterozygous for the ARSA p.L300S variant - thought to be a potential risk factor.
Also analysed 92 cases with familial dominant Parkinson's disease. ARSA p.N352S was found to be a protective variant (more common in controls than PD cohort).
"ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein." In cell lines, authors showed that ARSA deficiency correlates with an increase in α-synuclein aggregation.
Parkinson Disease and Complex Parkinsonism v1.128 ARSA Ida Ertmanska changed review comment from: PMID: 37381728 Senkevich et al., 2023
Authors performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by meta-analysis, and found evidence for associations between rare functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each). Of note: "results should be interpreted with caution as no association survived multiple comparisons correction."

p.L300V variant found in two cases and one control

Also found potential co-segregation of p.E382K variant in two unrelated PD patients with history of MLD and PD. However, one of the patients, II-4 from the first family, was also a carrier of the GBA1 variant RecNcil - which impossible to estimate the role of the ARSA variant in PD. The variant was not found in any controls.
Caveat: the variant is referred to as p.E382K and p.E384K in different parts of the publication. Likely to be the c.1150G>A, p.Glu384Lys variant - MAF = 0.00005331 in gnomAD v4.1.1., no homozygotes. P/LP classification in ClinVar.

PMID: 31312839 Lee et al., 2019
"ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein."; to: PMID: 37381728 Senkevich et al., 2023
Authors performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by meta-analysis, and found evidence for associations between rare functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each). Of note: "results should be interpreted with caution as no association survived multiple comparisons correction."

Authors also found potential co-segregation of p.E382K variant in two unrelated PD patients with history of MLD and PD. The variant was not found in any controls.
Family A, patient II-4 - 62yo, had Parkinson's disease, het for p.E382K; also a carrier of the GBA1 variant RecNcil - hence, impossible to estimate the role of the ARSA variant in PD.
Family A, individual IV-1 - 12yo, diagnosed with MLD, comp het for ARSA variants p.E382K and c.465G>T, p.Q155H.
Caveat: variant p.E382K = c.1150G>A, p.Glu384Lys (p.E384K) - MAF = 0.00005331 in gnomAD v4.1.1., no homozygotes. P/LP classification in ClinVar.
Family B: 5 family members with Parkinson's disease, 4 deceased and not genotyped (77-82yrs), individual II-4 (72yo) had PD and was ARSA wt/wt. Individual IV-1: 7yo, MLD diagnosis, comp het for ARSA variants p.E382K and c.1107+1G>A. Other het p.E382K carriers are aged under 60yo so not known if they will be affected by PD.

p.L300V variant found in two cases and one controls

PMID: 31312839 Lee et al., 2019
"ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein."
Parkinson Disease and Complex Parkinsonism v1.128 ARSA Ida Ertmanska changed review comment from: PMID: 37381728 Senkevich et al., 2023
Authors performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by meta-analysis, and found evidence for associations between rare functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each). Of note: "results should be interpreted with caution as no association survived multiple comparisons correction."

PMID: 31312839 Lee et al., 2019
"ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein."; to: PMID: 37381728 Senkevich et al., 2023
Authors performed burden analyses in six independent cohorts with 5801 PD patients and 20,475 controls, followed by meta-analysis, and found evidence for associations between rare functional ARSA variants and PD in four cohorts (P ≤ 0.05 in each). Of note: "results should be interpreted with caution as no association survived multiple comparisons correction."

p.L300V variant found in two cases and one control

Also found potential co-segregation of p.E382K variant in two unrelated PD patients with history of MLD and PD. However, one of the patients, II-4 from the first family, was also a carrier of the GBA1 variant RecNcil - which impossible to estimate the role of the ARSA variant in PD. The variant was not found in any controls.
Caveat: the variant is referred to as p.E382K and p.E384K in different parts of the publication. Likely to be the c.1150G>A, p.Glu384Lys variant - MAF = 0.00005331 in gnomAD v4.1.1., no homozygotes. P/LP classification in ClinVar.

PMID: 31312839 Lee et al., 2019
"ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein."
Parkinson Disease and Complex Parkinsonism v1.128 GBA Anjali Lloyd-Jani reviewed gene: GBA: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 29385658; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Parkinson Disease and Complex Parkinsonism v1.108 GBA Sarah Leigh changed review comment from: The new_gene_name tag has been added. The new name for GBA is GBA1.; to: Added new-gene-name tag, new approved HGNC gene symbol for GBA is GBA1.
Parkinson Disease and Complex Parkinsonism v1.108 GBA Sarah Leigh Tag new-gene-name tag was added to gene: GBA.
Parkinson Disease and Complex Parkinsonism v1.108 GBA Sarah Leigh commented on gene: GBA
Parkinson Disease and Complex Parkinsonism v1.66 GBA Alison Callaway changed review comment from: 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 outweigh these issues?; to: 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?
Parkinson Disease and Complex Parkinsonism v1.66 GBA Alison Callaway changed review comment from: 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 PD cases outweigh these issues?; to: 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 outweigh these issues?
Parkinson Disease and Complex Parkinsonism v1.66 GBA Alison Callaway reviewed gene: GBA: Rating: RED; Mode of pathogenicity: None; Publications: 29385658; Phenotypes: ; Mode of inheritance: None
Parkinson Disease and Complex Parkinsonism GBA Ellen McDonagh classified GBA as Green List (high evidence)
Parkinson Disease and Complex Parkinsonism GBA alisdair mcneill reviewed GBA
Parkinson Disease and Complex Parkinsonism GBA Arianna Tucci reviewed GBA
Parkinson Disease and Complex Parkinsonism GBA Ellen McDonagh classified GBA as amber
Parkinson Disease and Complex Parkinsonism GBA Ellen McDonagh marked GBA as ready
Parkinson Disease and Complex Parkinsonism GBA Ellen McDonagh classified GBA as red
Parkinson Disease and Complex Parkinsonism GBA Ellen McDonagh commented on GBA