Increased yield of full GBA sequencing in Ashkenazi Jews with Parkinson's disease

Jennifer A Ruskey¹, Lior Greenbaum², Léanne Roncière³, Armaghan Alam⁴, Dan Spiegelman¹, Christopher Liong⁵, Oren A Levy⁶, Cheryl Waters⁵, Stanley Fahn⁵, Karen S Marder⁶, Wendy Chung⁷, Gilad Yahalom⁸, Simon Israeli-Korn⁹, Vered Livneh⁹, Tsvia Fay-Karmon⁹, Roy N Alcalay⁶, Sharon Hassin-Baer⁸, Ziv Gan-Or¹⁰

Affiliations

¹ Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada.
² The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel; The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
³ Faculty of Medicine, McGill University, Montréal, Quebec, Canada.
⁴ Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada.
⁵ Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
⁶ Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
⁷ Department of Pediatrics and Medicine, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
⁸ Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Department of Neurology, Sheba Medical Center, Tel Hashomer, Israel; Movement Disorders Institute, Sheba Medical Center, Tel Hashomerf, Israel.
⁹ Department of Neurology, Sheba Medical Center, Tel Hashomer, Israel; Movement Disorders Institute, Sheba Medical Center, Tel Hashomerf, Israel.
¹⁰ Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada; Department of Human Genetics, McGill University, Montréal, Quebec, Canada. Electronic address: ziv.gan-or@mcgill.ca.

PMID: 29842932
PMCID: PMC6261782
DOI: 10.1016/j.ejmg.2018.05.005

Increased yield of full GBA sequencing in Ashkenazi Jews with Parkinson's disease

Jennifer A Ruskey et al. Eur J Med Genet. 2019 Jan.

. 2019 Jan;62(1):65-69.

doi: 10.1016/j.ejmg.2018.05.005. Epub 2018 May 26.

Authors

Affiliations

¹ Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada.
² The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel; The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
³ Faculty of Medicine, McGill University, Montréal, Quebec, Canada.
⁴ Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada.
⁵ Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
⁶ Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
⁷ Department of Pediatrics and Medicine, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
⁸ Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Department of Neurology, Sheba Medical Center, Tel Hashomer, Israel; Movement Disorders Institute, Sheba Medical Center, Tel Hashomerf, Israel.
⁹ Department of Neurology, Sheba Medical Center, Tel Hashomer, Israel; Movement Disorders Institute, Sheba Medical Center, Tel Hashomerf, Israel.
¹⁰ Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada; Department of Human Genetics, McGill University, Montréal, Quebec, Canada. Electronic address: ziv.gan-or@mcgill.ca.

PMID: 29842932
PMCID: PMC6261782
DOI: 10.1016/j.ejmg.2018.05.005

Abstract

Background: Variants in GBA are the most common genetic risk factor for Parkinson's disease (PD), and are especially prevalent in the Ashkenazi Jewish (AJ) population. However, most studies on GBA in AJ genotype only seven selected Gaucher-associated pathogenic variants rather than sequencing the whole gene, which may leave carriers of PD-associated GBA variants undiscovered.

Methods: GBA was fully sequenced using molecular inversion probes (MIPs) and Sanger sequencing in 735 AJ PD patients and 662 AJ controls, from Israel and New York. Additional AJ control data (n = 3044) from the Inflammatory Bowel Disease Exome Portal was used.

Results: Full GBA sequencing increased the number of variants discovered by 17.4%, compared to targeted genotyping. An additional 17 PD patients were identified with GBA-associated PD. The p.E326K variant was found in 1.6% of AJ PD patients, making it the second most common PD-associated GBA variant in AJ. GBA variants were found in 18% of PD patients and 7.5% of controls (OR = 2.7, 95%CI = 1.9-3.8, p < 0.0001).

Conclusion: Without full sequencing of GBA, or at minimum including p.E326K in the genotyping panel, a significant proportion of variant carriers go undiscovered and may be incorrectly assigned as non-carriers in studies or clinical trials.

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References

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Increased yield of full GBA sequencing in Ashkenazi Jews with Parkinson's disease

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Increased yield of full GBA sequencing in Ashkenazi Jews with Parkinson's disease

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