Research On Genetics And Genotype-phenotype Correlation Of Dystonia

Part 1 Exploration of Genetic Spectrum and Genotype-phenotype correlation in Dystonia PatientsBackground:Dystonia is a movement disorder with high clinical and genetic heterogeneity.Molecular diagnosis is important for an accurate diagnosis of dystonia.The genetic spectrum and genotype-phenotype correlation of dystonia in China are still unclear.Objectives and Methods:To explore the genetic spectrum and genotype-phenotype correlation of dystonia,we performed next-generation sequencing in dystonia patients from China.Sanger sequencing was utilized to substantiate the findings.The effects of identified variants were classified according to the American College of Medical Genetics and Genomics(ACMG)standards and guidelines.Results:A total of 93 patients(42 female and 51 male)were recruited in this study.The mean age at onset was 25.1 ± 14.0 years ranging from 2 to 59 years.Among these patients,41(41/93,44.1%)had focal dystonia,28(28/93,30.1%)had segmental dystonia,3(3/93,3.2%)had multifocal dystonia,21(21/93,22.6%)had generalized dystonia.29 patients(29/93,31.2%)were identified with mutations in dystonia-associated genes,including TORlA(10/93,10.8%),THAP1(3/93,3.2%),GCH1(5/93,5.4%),TH(2/93,2.2%),SGCE(2/93,2.2%),ATP1A3(3/93,3.20%),AN03(2/93,2.2%)and GNAL(2/93,2.2%).According to ACMG standards and guidelines,of 93 patients,14 were identified with pathogenic variants(14/93,15.1%),and another 7 were identified with likely-pathogenic variants(7/93,7.5%).Another eight patients(8/93,8.6%)were identified with variants which were considered to be VUS.Conclusions:The most common causive gene of dystonia in this study was TORlA,followed by GCH1 and THAP1.The genotype-phenotype correlation was consistent with previous reports,and some genes showed heterogeneity of phenotype.Part 2 Genotype and Phenotype features of DYT-TOR1A Dystonia in Chinese PopulationObjective:To describe the genotype and phenotype features of DYT-TOR1A dystonia in Chinese population.Methods:Clinical data of the TOR1A positive patients in our center from 2009 to 2017 were retrospectively analyzed.At the same time,we recruited the TORI A positive patients in Chinese population searched in Pubmed,CNKI,and Wanfang databases.Clinical data and genetic features of all TORIA positive patients were comprehensive analyzed.Results:Thirty-two TORIA positive cases in our center and 9 TORIA positive patients with detailed clinical data in the literature were recruited and divided into GAGdel group and non-GAGdel group.The GAGdel group included 39 patients with an average onset age of 14.518.5(4-41)years.Limb-onset was the most common,with 15 cases(12/39,38.5%)in the upper extremities,12 cases(12/39,30.8%)in the lower extremities.Generalized dystonia was the most common subtype(24/39,61.5%),followed by segmental dystonia(11/39,28.2%).The ages at onset of two patients in the non-GAGdel group were 24 years and 45 years respectively.The onset sites were neck and eyelid respectively.The former patient showed segmental dystonia and the latter showed focal dystonia.Conclusion:Most TOR1A-positive patients carried the classic variant p.Glu303del whereas only a few patients harbored other types of variants.The DYT-TORlA patients in Chinese population had similar clinical characteristics to those in western populations,including mostly early onset age,common onset of limbs,and generalized and segmental dystonia in distribution.