Novel mutations uncovered from exome sequencing of Norwegian families with Parkinson's disease. M. Lin1, J. Aasly2, D. Evans1, C. Vilarino-Guell1, B. Shah1, C. Szu Tu1, H. Han1, H. Sherman1, C. Thompson1, M. Toft3, K. Wirdefeldt4, A. C. Belin5, M. S. Petersen6, J. Trinh1, V. Silva1, F. Pishotta1, M. Farrer1, GEO-PD Consortium 1) Centre for Applied Neurogenetics, University of British Columbia, Vancouver, BC, Canada; 2) Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway; 3) Department of Neurology, Oslo University Hospital, Oslo, Norway; 4) Department of Medical Epidemiology and Biostatistics and Department of Clinical Neuroscience, Karolinska Instiutet, Stockholm, Sweden; 5) Department of Neuroscience, Karolinska Instiutet, Stockholm, Sweden; 6) Department of Occupational Medicine and Public Health, The Faroese Hospital System, Torshavn, Faroe Islands.

   Approximately 14% of patients with Parkinson's disease (PD) have a family history of parkinsonism. In larger, multi-incident families, pathogenic mutations/genes have now been identified using traditional linkage and contemporary exome sequencing methods. We report a clinical and comparative genetic study of Norwegian families. Six Norwegian families (pedigree structure of 3-5 generations, 111 individuals, of whom 28 have parkinsonism) were invited; 25 affected (mean age 76.3 9.9 SD, mean age of onset 61.1 7.0 SD, range = 45-75 years) and 16 (mean age 70.8 16.1 SD) unaffected members participated in the study. Late-onset, asymmetric, levodopa-responsive PD appears to segregate in an autosomal dominant fashion. Two to three affected members (cousins) from each pedigree were screened negative for known genetic mutations using a proprietary diagnostic panel, then further exome-sequenced on an Illumina HiSeq platform. Genome alignment, annotation and pair-wise bioinformatic comparisons of affected family members were performed. Coding variants observed at <1% frequency were validated by Sanger sequencing in all family members and matched control subjects. Mutations segregating with PD but not observed in controls were genotyped in 3112 subjects (1613 patients) of Scandinavian origin. Subsequently, mutations were genotyped in multi-ethnic GEO-PD samples using Sequenom and TaqMan technologies. Additional exonic sequencing was performed in candidate genes. Our preliminary data showed one mutation in each family, for four families, which segregates with PD in four genes (NOVA2, PABPC1L, RPE65 and OR56B4). Each mutation was highly conserved through evolution, and those substitutions were predicted to have deleterious consequences on protein function. Mutations in PABPC1L, RPE65 and OR56B4 were observed in additional unrelated patients but not control subjects. The functions of the encoded proteins are not well characterized but are involved in RNA splicing in developing neurons, translation, retinal regeneration and olfaction. In conclusion, pair-wise exome-sequencing is an efficient method to identify novel gene mutations in familial PD that enhances traditional linkage efforts in disease gene mapping.

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