title: A systematic screening to identify de novo mutations causing sporadic early-onset Parkinson's disease.
abstract: 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.
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3AR, UK.
authors.forename: Celia
authors.initials: C
authors.lastname: Kun-Rodrigues
authors.affiliation: Department of Neurology, University Medical Center Hamburg-Eppendorf (UKE), Hamburg 20246, Germany, Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, University College London, London WC1N 3BG, UK.
authors.forename: Christos
authors.initials: C
authors.lastname: Ganos
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3AR, UK.
authors.forename: Rita
authors.initials: R
authors.lastname: Guerreiro
authors.affiliation: Department of Neurology, University Hospital Schleswig Holstein, Campus Kiel 24105, Germany.
authors.forename: Susanne A
authors.initials: SA
authors.lastname: Schneider
authors.affiliation: German Center for Neurodegenerative Diseases, Tübingen, Germany, Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen 72076, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Schulte
authors.affiliation: INSERM U M27, Pitié-Salpêtrière Hospital, Brain and Spinal Cord Institute (ICM), Paris 75013, France.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lesage
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3AR, UK.
authors.forename: Lee
authors.initials: L
authors.lastname: Darwent
authors.affiliation: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK and.
authors.forename: Peter
authors.initials: P
authors.lastname: Holmans
authors.affiliation: Laboratory of Neurogenetics, National Institutes on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, University College London, London WC1N 3BG, UK.
authors.forename: Kailash
authors.initials: K
authors.lastname: Bhatia
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3AR, UK, j.bras@ucl.ac.uk.
authors.forename: Jose
authors.initials: J
authors.lastname: Bras
mesh_terms: D000328:Adult; D053501:Arsenite Transporting ATPases / Q000235:genetics; D004252:DNA Mutational Analysis; D059472:Exome; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D060066:Protein Interaction Maps; D033921:Vesicular Transport Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: C489667:GET3 protein, human; C496748:VAPB protein, human; D033921:Vesicular Transport Proteins; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D053501:Arsenite Transporting ATPases