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.
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Acknowledgements
We thank the Bachmann-Strauss Dystonia & Parkinson Foundation through a Jake’s Ride for Dystonia Research Grant (to AW) and the Fritz Thyssen Foundation (to AW) for funding our experiments. AD is the recipient of a scholarship from the German Academic Exchange Program (DAAD). CK is a Schilling Professor of Neurogenetics (Herman and Lilly Schilling Foundation). We would like to thank the following members of the XDP Study Group of the Philippines who assisted in collecting XDP patients and assembling control cohorts: Dr Abundio Balgos, Dr Cid Czarina Diesta, Dr Criscely Go, Dr Arlene Ng, Dr Anthony Piano, Dr Marita VT Reyes, Dr Sonia Sarcia, and Mercy Joyce Monding-Yabres.
Abbreviations
XDP, X-linked dystonia-parkinsonism; DSC, disease-specific single-nucleotide change; SNV, single-nucleotide variation; CNV, copy number variant; STR, Short-tandem repeat; NGS, next-generation sequencing, in this text refers to genome sequencing; TAF1, TATA box-binding protein-associated factor 1 gene; OGT, O-linked β-N-acetylglucosamine transferase gene; ACRC, acidic repeat-containing protein gene; CXCR3, chemokine receptor 3 gene; SVA, SINE-VNTR-Alu element.
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CK is a medical counselor to Centogene, a commercial genetic testing center based in Rostock, Germany. The remaining authors declare no conflict of interest.
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Domingo, A., Westenberger, A., Lee, L. et al. New insights into the genetics of X-linked dystonia-parkinsonism (XDP, DYT3). Eur J Hum Genet 23, 1334–1340 (2015). https://doi.org/10.1038/ejhg.2014.292
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DOI: https://doi.org/10.1038/ejhg.2014.292
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