A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants

Manu Sharma, John P.A. Ioannidis, Jan O. Aasly, Grazia Annesi, Alexis Brice, Lars Bertram, Maria Bozi, Maria Barcikowska, David Crosiers, Carl E. Clarke, Maurizio F. Facheris, Matthew Farrer, Gaetan Garraux, Suzana Gispert, Georg Auburger, Carles Vilariño-Güell, Georgios M. Hadjigeorgiou, Andrew A. Hicks, Nobutaka Hattori, Beom S. JeonZygmunt Jamrozik, Anna Krygowska-Wajs, Suzanne Lesage, Christina M. Lill, Juei Jueng Lin, Timothy Lynch, Peter Lichtner, Anthony E. Lang, Cecile Libioulle, Miho Murata, Vincent Mok, Barbara Jasinska-Myga, George D. Mellick, Karen E. Morrison, Thomas Meitnger, Alexander Zimprich, Grzegorz Opala, Peter P. Pramstaller, Irene Pichler, Sung Sup Park, Aldo Quattrone, Ekaterina Rogaeva, Owen A. Ross, Leonidas Stefanis, Joanne D. Stockton, Wataru Satake, Peter A. Silburn, Tim M. Strom, Jessie Theuns, Eng King Tan, Tatsushi Toda, Hiroyuki Tomiyama, Ryan J. Uitti, Christine Van Broeckhoven, Karin Wirdefeldt, Zbigniew Wszolek, Georgia Xiromerisiou, Harumi S. Yomono, Kuo Chu Yueh, Yi Zhao, Thomas Gasser, Demetrius Maraganore, Rejko Krüger

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Abstract

Background Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease. Although additional missense variants were described, their pathogenic role yet remains inconclusive. Methods and results We performed the largest multicenter study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort. Conclusions Our study apart from identifying the p. Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.

Original languageEnglish (US)
Pages (from-to)721-726
Number of pages6
JournalJournal of medical genetics
Volume49
Issue number11
DOIs
StatePublished - Nov 2012

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Sharma, M., Ioannidis, J. P. A., Aasly, J. O., Annesi, G., Brice, A., Bertram, L., Bozi, M., Barcikowska, M., Crosiers, D., Clarke, C. E., Facheris, M. F., Farrer, M., Garraux, G., Gispert, S., Auburger, G., Vilariño-Güell, C., Hadjigeorgiou, G. M., Hicks, A. A., Hattori, N., ... Krüger, R. (2012). A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants. Journal of medical genetics, 49(11), 721-726. https://doi.org/10.1136/jmedgenet-2012-101155