The <i>GBA</i> p.Trp378Gly mutation is a probable French‐Canadian founder mutation causing Gaucher disease and synucleinopathies

Ruskey, Jennifer A.; Zhou, Sirui; Santiago, Raoul; Franche, L.-A.; Alam, Armaghan; Roncière, Léanne; Spiegelman, Dan; Fon, Edward A.; Trempe, Jean‐François; Kalia, Lorraine V.; Postuma, Ronald B.; Dupré, Nicolas; Rivard, Georges‐Étienne; Assouline, Sarit; Amato, Dominick; Gan‐Or, Ziv

doi:10.1111/cge.13405

Cited by 10 publications

(7 citation statements)

References 34 publications

(42 reference statements)

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“…GBA was fully sequenced as previously described, 20 and the full protocol is available upon request. In brief, molecular inversion probes (MIPs) targeting the coding sequence of GBA were designed, and next generation sequencing (NGS) was performed post capture.…”

Section: Methodsmentioning

confidence: 99%

GBA variants in REM sleep behavior disorder: a multicenter study

Krohn

Ruskey

Rudakou

et al. 2019

Preprint

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Objective: To study the role of GBA variants in the risk for isolated rapid-eye-movement (REM)-sleep behavior disorder (iRBD) and conversion to overt neurodegeneration. Methods: A total of 4,147 individuals were included: 1,061 iRBD patients and 3,086 controls. GBA was fully sequenced using molecular inversion probes and Sanger sequencing. We analyzed the effects of GBA variants on the risk for iRBD, age at onset (AAO) and conversion rates. Results: GBA variants were found in 9.5% of iRBD patients compared to 4.1% in controls (odds ratio [OR]=2.45, 95% CI=1.87-3.22, p=1x10-10). The estimated OR for mild p.N370S variant carriers was 3.69, 95% CI=1.90-7.14, p=3.5x10-5, while for severe variant carriers it was 17.55, 95% CI=2.11-145.9, p=0.0015. Carriers of severe GBA variants had an average AAO of 52.8 years, 7-8 years earlier than those with mild variants or non-carriers (p=0.029). Of the GBA variant carriers with available data, 52.5% had converted, compared to 35.6% in non-carriers (p=0.011), with a trend for faster conversion among severe GBA variant carriers. However, the results on AAO and conversion were based on small numbers and should be taken with caution. Conclusions: GBA variants robustly and differentially increase the risk of iRBD. The rate of conversion to neurodegeneration is also increased and may be faster among severe GBA variant carriers, although confirmation will be required in larger samples. Screening for RBD in healthy carriers of GBA variants should be studied as a potential way to identify GBA variant carriers who will develop a synucleinopathy in the future.

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Section: Methodsmentioning

confidence: 99%

GBA variants in REM sleep behavior disorder: a multicenter study

Krohn

Ruskey

Rudakou

et al. 2019

Preprint

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“…In addition, other data are being collected for all patients, or in some cases for subgroups of patients, such as genetic, imaging, neuropsychological and neuropsychiatric data etc. Genetic data are being collected from all patients for whom DNA is available (currently >800 patients, out of >1,200 patients that have been enrolled by the completion of this paper), including genotyping using a custom single nucleotide polymorphism (SNP) array with >700,000 SNPs (Backbone of the OmniExpress array with custom content of the NeuroX SNP-chop, Illumina, Inc.), and targeted next generation sequencing of ∼50 PD-related genes, including GBA, LRRK2, SNCA, MAPT and others [23][24][25]. For a large number of patients (currently 400), peripheral blood mononuclear cells (PBMCs) are being collected, and iPSCs and neuronal models are being generated by the MNI-iPSC platform (https://mniopenresearch.org/articles/3-1) for specific studies as required.…”

Section: The Quebec Parkinson Network Cohort As An Open-access Reprementioning

confidence: 99%

“…Targeted next generation sequencing of candidate genes in patients with PD and healthy controls has supported roles for specific genetic variants in the pathogenesis of the disease, such as variants in GCH1 [42], MAPT [23], and SMPD1 [43], and demonstrated lack of association with other genes [44][45][46]. Furthermore, recruiting patients from the QPN Participant Registry provides an opportunity to access a large number of patients who are of French-Canadian ancestry, which was critical for the recent identification of a founder mutation in the GBA gene in French-Canadian patients with PD or RBD [25]. Genome-wide association study (GWAS) data from QPN patients have also been used for recent largescale genetic analyses of mitochondria-related genes and GWAS of AAO in PD [47,48].…”

Section: Recent Studies and Trials Facilitated By The Quebec Parkinsomentioning

confidence: 99%

The Quebec Parkinson Network: A Researcher-Patient Matching Platform and Multimodal Biorepository

Gan‐Or

Rao

Léveillé

et al. 2020

JPD

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Background: Genetic, biologic and clinical data suggest that Parkinson's disease (PD) is an umbrella for multiple disorders with clinical and pathological overlap, yet with different underlying mechanisms. To better understand these and to move towards neuroprotective treatment, we have established the Quebec Parkinson Network (QPN), an open-access patient registry, and data and bio-samples repository. Objective: To present the QPN and to perform preliminary analysis of the QPN data. Methods: A total of 1,070 consecutively recruited PD patients were included in the analysis. Demographic and clinical data were analyzed, including comparisons between males and females, PD patients with and without RBD, and stratified analyses comparing early and late-onset PD and different age groups. Results: QPN patients exhibit a male:female ratio of 1.8:1, an average age-at-onset of 58.6 years, an age-at-diagnosis of 60.4 years, and average disease duration of 8.9 years. REM-sleep behavior disorder (RBD) was more common among men, and RBD was associated with other motor and non-motor symptoms including dyskinesia, fluctuations, postural hypotension and hallucinations. Older patients had significantly higher rates of constipation and cognitive impairment, and longer disease duration was associated with higher rates of dyskinesia, fluctuations, freezing of gait, falls, hallucinations and cognitive impairment. Since QPN's creation, over 60 studies and 30 publications have included patients and data from the QPN. Conclusions: The QPN cohort displays typical PD demographics and clinical features. These data are open-access upon application (http://rpq-qpn.ca/en/), and will soon include genetic, imaging and bio-samples. We encourage clinicians and researchers to perform studies using these resources.

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“…Interestingly, a few recurrent GBA mutations, including p.N409S in Ashkenazi Jewish and European communities [12], p.D448H in northern Swedish [13], p.W417G in French-Canadian [14], and p.G416S in Tabuleiro do Norte, Northeastern Brazilian [15] populations have been suggested as founder mutations.…”

Section: Introductionmentioning

confidence: 99%

The GBA p.G85E mutation in Korean patients with non-neuronopathic Gaucher disease: founder and neuroprotective effects

Kim

Choi

Kim

et al. 2020

Preprint

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Background Gaucher disease (GD) is caused by a deficiency of β-glucocerebrosidase, encoded by GBA. Haplotype analyses previously demonstrated founder effects for particular GBA mutations in Ashkenazi Jewish and French-Canadian populations. This study aimed to investigate the clinical characteristics and mutation spectrum of GBA in Korean GD patients and to identify founder effect of GBA p.G85E in non-neuronopathic GD patients. Results The study cohort included 62 GD patients from 58 unrelated families. Among them, 18 patients from 17 families harbored the p.G85E mutation. Haplotype analysis was performed for 9 probands and their parents for whom DNA samples were available. In 58 unrelated probands, the GBA mutation p.L483P was the most common (30/116 alleles, 26%), followed by p.G85E (16%), p.F252I (13%), and p.R296Q (9%). The median age at diagnosis of the 18 patients harboring the p.G85E mutation was 3.8 (range 1.2–57) years. No patients developed neurological symptoms during follow-up periods of 2.2–20.3 (median 13.9) years. The size of the shared haplotype containing GBA p.G85E was 732 kbp, leading to an estimated age of 3,075 years. ConclusionThe GBA p.G85E mutation, which appears to be neuroprotective despite producing distinctive visceromegaly and skeletal symptoms, exhibited a potential founder effect in Korean GD patients.

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The GBA p.Trp378Gly mutation is a probable French‐Canadian founder mutation causing Gaucher disease and synucleinopathies

Cited by 10 publications

References 34 publications

GBA variants in REM sleep behavior disorder: a multicenter study

GBA variants in REM sleep behavior disorder: a multicenter study

The Quebec Parkinson Network: A Researcher-Patient Matching Platform and Multimodal Biorepository

The GBA p.G85E mutation in Korean patients with non-neuronopathic Gaucher disease: founder and neuroprotective effects

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