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. Jeon; Zygmunt 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

doi:10.1136/jmedgenet-2012-101155

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 language	English (US)
Pages (from-to)	721-726
Number of pages	6
Journal	Journal of medical genetics
Volume	49
Issue number	11
DOIs	https://doi.org/10.1136/jmedgenet-2012-101155
State	Published - 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

Sharma, M, Ioannidis, JPA, Aasly, JO, Annesi, G, Brice, A, Bertram, L, Bozi, M, Barcikowska, M, Crosiers, D, Clarke, CE, Facheris, MF, Farrer, M, Garraux, G, Gispert, S, Auburger, G, Vilariño-Güell, C, Hadjigeorgiou, GM, Hicks, AA, Hattori, N, Jeon, BS, Jamrozik, Z, Krygowska-Wajs, A, Lesage, S, Lill, CM, Lin, JJ, Lynch, T, Lichtner, P, Lang, AE, Libioulle, C, Murata, M, Mok, V, Jasinska-Myga, B, Mellick, GD, Morrison, KE, Meitnger, T, Zimprich, A, Opala, G, Pramstaller, PP, Pichler, I, Park, SS, Quattrone, A, Rogaeva, E, Ross, OA, Stefanis, L, Stockton, JD, Satake, W, Silburn, PA, Strom, TM, Theuns, J, Tan, EK, Toda, T, Tomiyama, H, Uitti, RJ, Van Broeckhoven, C, Wirdefeldt, K, Wszolek, Z, Xiromerisiou, G, Yomono, HS, Yueh, KC, Zhao, Y, Gasser, T, Maraganore, D & 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, vol. 49, no. 11, pp. 721-726. https://doi.org/10.1136/jmedgenet-2012-101155

@article{d149c97eaded4ba6b43a376752815cf0,

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

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.",

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

year = "2012",

month = nov,

doi = "10.1136/jmedgenet-2012-101155",

language = "English (US)",

volume = "49",

pages = "721--726",

journal = "Journal of medical genetics",

issn = "0022-2593",

publisher = "BMJ Publishing Group",

number = "11",

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TY - JOUR

T1 - A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants

AU - Sharma, Manu

AU - Ioannidis, John P.A.

AU - Aasly, Jan O.

AU - Annesi, Grazia

AU - Brice, Alexis

AU - Bertram, Lars

AU - Bozi, Maria

AU - Barcikowska, Maria

AU - Crosiers, David

AU - Clarke, Carl E.

AU - Facheris, Maurizio F.

AU - Farrer, Matthew

AU - Garraux, Gaetan

AU - Gispert, Suzana

AU - Auburger, Georg

AU - Vilariño-Güell, Carles

AU - Hadjigeorgiou, Georgios M.

AU - Hicks, Andrew A.

AU - Hattori, Nobutaka

AU - Jeon, Beom S.

AU - Jamrozik, Zygmunt

AU - Krygowska-Wajs, Anna

AU - Lesage, Suzanne

AU - Lill, Christina M.

AU - Lin, Juei Jueng

AU - Lynch, Timothy

AU - Lichtner, Peter

AU - Lang, Anthony E.

AU - Libioulle, Cecile

AU - Murata, Miho

AU - Mok, Vincent

AU - Jasinska-Myga, Barbara

AU - Mellick, George D.

AU - Morrison, Karen E.

AU - Meitnger, Thomas

AU - Zimprich, Alexander

AU - Opala, Grzegorz

AU - Pramstaller, Peter P.

AU - Pichler, Irene

AU - Park, Sung Sup

AU - Quattrone, Aldo

AU - Rogaeva, Ekaterina

AU - Ross, Owen A.

AU - Stefanis, Leonidas

AU - Stockton, Joanne D.

AU - Satake, Wataru

AU - Silburn, Peter A.

AU - Strom, Tim M.

AU - Theuns, Jessie

AU - Tan, Eng King

AU - Toda, Tatsushi

AU - Tomiyama, Hiroyuki

AU - Uitti, Ryan J.

AU - Van Broeckhoven, Christine

AU - Wirdefeldt, Karin

AU - Wszolek, Zbigniew

AU - Xiromerisiou, Georgia

AU - Yomono, Harumi S.

AU - Yueh, Kuo Chu

AU - Zhao, Yi

AU - Gasser, Thomas

AU - Maraganore, Demetrius

AU - Krüger, Rejko

PY - 2012/11

Y1 - 2012/11

N2 - 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.

AB - 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.

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U2 - 10.1136/jmedgenet-2012-101155

DO - 10.1136/jmedgenet-2012-101155

M3 - Article

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AN - SCOPUS:84870287920

SN - 0022-2593

VL - 49

SP - 721

EP - 726

JO - Journal of medical genetics

JF - Journal of medical genetics

IS - 11

ER -

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

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