title: New insights into the genetics of X-linked dystonia-parkinsonism (XDP, DYT3).
abstract: 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.
authors.affiliation: 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.
authors.forename: Aloysius
authors.initials: A
authors.lastname: Domingo
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Westenberger
authors.affiliation: XDP Study Group, Philippine Children's Medical Center, Quezon City, Philippines.
authors.forename: Lillian V
authors.initials: LV
authors.lastname: Lee
authors.affiliation: Institute for Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Brænne
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.|Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany.
authors.forename: Tian
authors.initials: T
authors.lastname: Liu
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Vater
authors.affiliation: XDP Study Group, Philippine Children's Medical Center, Quezon City, Philippines.|Faculty of Neurology and Psychiatry, University of Santo Tomas, Manila, Philippines.
authors.forename: Raymond
authors.initials: R
authors.lastname: Rosales
authors.affiliation: XDP Study Group, Philippine Children's Medical Center, Quezon City, Philippines.|Department of Neurosciences, University of the Philippines Manila-Philippine General Hospital, Manila, Philippines.
authors.forename: Roland Dominic
authors.initials: RD
authors.lastname: Jamora
authors.affiliation: XDP Study Group, Philippine Children's Medical Center, Quezon City, Philippines.|Department of Neurosciences, University of the Philippines Manila-Philippine General Hospital, Manila, Philippines.
authors.forename: Paul Matthew
authors.initials: PM
authors.lastname: Pasco
authors.affiliation: XDP Study Group, Philippine Children's Medical Center, Quezon City, Philippines.|Institute of Human Genetics, National Institutes of Health-University of the Philippines Manila, Manila, Philippines.
authors.forename: Eva Maria
authors.initials: EM
authors.lastname: Cutiongco-Dela Paz
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Freimann
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
authors.forename: Thomas Gpm
authors.initials: TG
authors.lastname: Schmidt
authors.affiliation: Movement Disorders Section, Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Dressler
authors.affiliation: Section of Functional Genetics, Institute of Human Genetics, University of Lübeck, Lübeck, Germany.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Kaiser
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.|School of Public Health, Faculty of Medicine, Imperial College, London, UK.
authors.forename: Lars
authors.initials: L
authors.lastname: Bertram
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Erdmann
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Lohmann
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
mesh_terms: D000328:Adult; D000368:Aged; D002874:Chromosome Mapping / Q000379:methods; D041321:Chromosomes, Human, X / Q000235:genetics*; D020821:Dystonic Disorders / Q000235:genetics*; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D008040:Genetic Linkage / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D010679:Philippines; D011110:Polymorphism, Genetic / Q000235:genetics