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Hum Mol Genet. 2015 Dec 1;24(23):6711-20. doi: 10.1093/hmg/ddv376. Epub 2015 Sep 11.

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

Author information

1
Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3AR, UK.
2
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.
3
Department of Neurology, University Hospital Schleswig Holstein, Campus Kiel 24105, Germany.
4
German Center for Neurodegenerative Diseases, Tübingen, Germany, Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen 72076, Germany.
5
INSERM U M27, Pitié-Salpêtrière Hospital, Brain and Spinal Cord Institute (ICM), Paris 75013, France.
6
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK and.
7
Laboratory of Neurogenetics, National Institutes on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
8
Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, University College London, London WC1N 3BG, UK.
9
Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3AR, UK, j.bras@ucl.ac.uk.

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.

PMID:
26362251
PMCID:
PMC4634375
DOI:
10.1093/hmg/ddv376
[Indexed for MEDLINE]
Free PMC Article

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