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Kun-Rodrigues, C.* ; Ganos, C.* ; Guerreiro, R.* ; Schneider, S.A.* ; Schulte, C.* ; Lesage, S.* ; Darwent, L.* ; Holmans, P.* ; Singleton, A.* ; International Parkinson's Disease Genomics Consortium (IPDGC) (Illig, T. ; Lichtner, P.) ; Bhatia, K.* ; Bras, J.*

A systematic screening to identify de novo mutations causing sporadic early-onset Parkinson's disease.

Hum. Mol. Genet. 24, 6711-6720 (2015)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Despite the many advances in our understanding of the genetic basis of Mendelian forms of Parkinson's disease (PD), a large number of early-onset cases still remain to be explained. Many of these cases, present with a form of disease that is identical to that underlined by genetic causes, but do not have mutations in any of the currently known disease-causing genes. Here, we hypothesized that de novo mutations may account for a proportion of these early-onset, sporadic cases. We performed exome sequencing in full parent-child trios where the proband presents with typical PD to unequivocally identify de novo mutations. This approach allows us to test all genes in the genome in an unbiased manner. We have identified and confirmed 20 coding de novo mutations in 21 trios. We have used publicly available population genetic data to compare variant frequencies and our independent in-house dataset of exome sequencing in PD (with over 1200 cases) to identify additional variants in the same genes. Of the genes identified to carry de novo mutations, PTEN, VAPB and ASNA1 are supported by various sources of data to be involved in PD. We show that these genes are reported to be within a protein-protein interaction network with PD genes and that they contain additional rare, case-specific, mutations in our independent cohort of PD cases. Our results support the involvement of these three genes in PD and suggest that testing for de novo mutations in sporadic disease may aid in the identification of novel disease-causing genes.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 0964-6906
e-ISSN 1460-2083
Journal Human Molecular Genetics
Quellenangaben Volume: 24, Issue: 23, Pages: 6711-6720 Article Number: , Supplement: ,
Publisher Oxford University Press
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology II (EPI2)
Institute of Human Genetics (IHG)