Objective: To reveal molecular epidemiology of hereditary dystonia through resequencing of the currently-known dystonia genes and identification of novel genetic defects.

Background: The Japan Dystonia Consortium was established to construct a nationwide clinical and DNA database on dystonia patients, including genotype-phenotype-outcome correlations and natural course, which would contribute to elucidation of dystonia pathomechanism and refinement of guideline for dystonia.

Methods: A total of 587 patients with dystonia or other movement disorders were recruited. Patients were videotaped, which were phenomenologically examined by movement disorder specialists with long-standing experience. After phenomenological evaluation, candidate genes are chosen for sequence analysis. Direct sequencing of polymerase chain reaction products with the Sanger-based method or whole-exome sequencing was applied for genetic screening in the currently-known dystonia genes. Furthermore, whole exome trio sequencing was conducted in order to identify new genetic defect(s) in dystonia.

Results: Mutations in DYT genes have been revealed in familial and seemingly sporadic cases with dystonia, including DYT-TOR1A, DYT-THAP1, DYT-GNAL, DYT/PARK-GCH1, DYT/PARK-TH, DYT/PARK-ATP1A3, DYT/PARK-TAF1, and DYT-SGCE. In addition, we identified mutations in other dystonia or dyskinesia-associated genes, including PRRT2, MR-1, TUBB4A, KMT2B and ADCY5. Genotype –phenotype correlations in most cases were consistent with those previously reported.

Conclusions: The cohort contains enough sample power to detect novel genes for dystonia. Correct phenomenological evaluation is indispensable for variant interpretation and establishment of phenotype-genotype correlations.

« Back to 2018 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/cohort-profile-of-the-japan-dystonia-consortium-genetic-diagnosis-and-characteristics-of-movement-disorders-in-japan/