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Eur J Hum Genet. 2015 Oct;23(10):1334-40. doi: 10.1038/ejhg.2014.292. Epub 2015 Jan 21.

New insights into the genetics of X-linked dystonia-parkinsonism (XDP, DYT3).

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Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
XDP Study Group, Philippine Children's Medical Center, Quezon City, Philippines.
Graduate School for Computing in Medicine and Life Sciences, University of Lübeck, Lübeck, Germany.
Institute for Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany.
Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany.
Institute of Human Genetics, Christian-Albrechts-University, Kiel, Germany.
Faculty of Neurology and Psychiatry, University of Santo Tomas, Manila, Philippines.
Department of Neurosciences, University of the Philippines Manila-Philippine General Hospital, Manila, Philippines.
Institute of Human Genetics, National Institutes of Health-University of the Philippines Manila, Manila, Philippines.
Movement Disorders Section, Department of Neurology, Hannover Medical School, Hannover, Germany.
Section of Functional Genetics, Institute of Human Genetics, University of Lübeck, Lübeck, Germany.
School of Public Health, Faculty of Medicine, Imperial College, London, UK.


X-linked recessive dystonia-parkinsonism is a rare movement disorder that is highly prevalent in Panay Island in the Philippines. Earlier studies identified seven different genetic alterations within a 427-kb disease locus on the X chromosome; however, the exact disease-causing variant among these is still not unequivocally determined. To further investigate the genetic cause of this disease, we sequenced all previously reported genetic alterations in 166 patients and 473 Filipino controls. Singly occurring variants in our ethnically matched controls would have allowed us to define these as polymorphisms, but none were found. Instead, we identified five patients carrying none of the disease-associated variants, and one male control carrying all of them. In parallel, we searched for novel single-nucleotide variants using next-generation sequencing. We did not identify any shared variants in coding regions of the X chromosome. However, by validating intergenic variants discovered via genome sequencing, we were able to define the boundaries of the disease-specific haplotype and narrow the disease locus to a 294-kb region that includes four known genes. Using microarray-based analyses, we ruled out the presence of disease-linked copy number variants within the implicated region. Finally, we utilized in silico analysis and detected no strong evidence of regulatory regions surrounding the disease-associated variants. In conclusion, our finding of disease-specific variants occurring in complete linkage disequilibrium raises new insights and intriguing questions about the origin of the disease haplotype, the existence of phenocopies and of reduced penetrance, and the causative genetic alteration in XDP.

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