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

• Published in: Journal of medical genetics Vol. 49; no. 11; pp. 721 - 6
• Main Authors: Sharma, Manu, Ioannidis, John P A, Aasly, Jan O, Annesi, Grazia, Brice, Alexis, Bertram, Lars, Bozi, Maria, Barcikowska, Maria, Crosiers, David, Clarke, Carl E, Facheris, Maurizio F, Farrer, Matthew, Garraux, Gaetan, Gispert, Suzana, Auburger, Georg, Vilariño-Güell, Carles, Hadjigeorgiou, Georgios M, Hicks, Andrew A, Hattori, Nobutaka, Jeon, Beom S, Jamrozik, Zygmunt, Krygowska-Wajs, Anna, Lesage, Suzanne, Lill, Christina M, Lin, Juei-Jueng, Lynch, Timothy, Lichtner, Peter, Lang, Anthony E, Libioulle, Cecile, Murata, Miho, Mok, Vincent, Jasinska-Myga, Barbara, Mellick, George D, Morrison, Karen E, Meitnger, Thomas, Zimprich, Alexander, Opala, Grzegorz, Pramstaller, Peter P, Pichler, Irene, Park, Sung Sup, Quattrone, Aldo, Rogaeva, Ekaterina, Ross, Owen A., Stefanis, Leonidas, Stockton, Joanne D, Satake, Wataru, Silburn, Peter A, Strom, Tim M, Theuns, Jessie, Tan, Eng- King, Toda, Tatsushi, Tomiyama, Hiroyuki, Uitti, Ryan J, Van Broeckhoven, Christine, Wirdefeldt, Karin, Wszolek, Zbigniew, Xiromerisiou, Georgia, Yomono, Harumi S, Yueh, Kuo-Chu, Zhao, Yi, Gasser, Thomas, Maraganore, Demetrius, Krüger, Rejko
• Format: Journal Article Web Resource
• Language: English
• Published: London BMJ Publishing Group Ltd 01.11.2012; BMJ Publishing Group; BMJ Publishing Group LTD
• Series: Short report
• Subjects: Biological and medical sciences; Complex traits; Consortia; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease; Female; Fundamental and applied biological sciences. Psychology; Genetic Association Studies; Genetic epidemiology; Genetic Predisposition to Disease; genetic processes; Genetics; Genetics & genetic processes; Genetics of eukaryotes. Biological and molecular evolution; Genome-wide; Genotype-Phenotype Correlations; Génétique & processus génétiques; Humans; Life sciences; Male; Medical genetics; Medical sciences; Molecular and cellular biology; Mutation; Neurology; Parkinson Disease - genetics; Parkinson's disease; Risk Factors; Sciences du vivant; Software; Vesicular Transport Proteins - genetics; Vesicular Transport Proteins - metabolism; White people; Greece; United States > US; Italy; Variant; Nervous system diseases; Gene; Gene penetrance; Central nervous system disease; Parkinson disease; Genetics; Degenerative disease; Cerebral disorder; Extrapyramidal syndrome
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmedgenet-2012-101155

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 multi-center 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.