Clinical Characteristics And Genetic Features Of Patients With Huntington’s Disease In China And HTT Haplotype Analysis

Background:Huntington’s disease(HD)is a dominantly inherited neurodegenerative disorder that results from the expansion of a CAG trinucleotide repeat in the first exon of the gene The prevalence of HD varies geographically.The highest figures reported in Caucasians were 4-10 per 100,000 people,and the lowest were in East Asians to be 0.1-0.5 per 100,000 people.Though many studies on HD have been carried out in the Caucasian population,there is a paucity of clinical phenotype and genotype description in the Chinese population.The low prevalence of HD may be associated with the haplotype around HTT gene region.Many researchers have built their own haplotype system in their populations,but there are few studies carried out in China.Section Ⅰ:Clinical and genetic features of patients with Huntington’s disease in ChinaAim:To describe the clinical and genetic features of HD in the Chinese population.Methods:A total of 322 persons with expanded CAG repeats were consecutively recruited between 2008 and 2018,from the neurologic clinics of three medical centers in Southeastern China.CAG repeat sizes were sequenced and clinical data were summarized.Results:Among 322 persons with HD,242 were symptomatic patients and 80 were asymptomatic mutation carriers.The mean age at onset(AAO)was 40.3±11.9 years and the mean expanded CAG repeat length was 46.1±7.5.For initial symptoms,88.8%(215/242)patients presented with movement symptoms,3.3%(8/242)with cognitive impairment,6.2%(15/242)with psychiatric symptoms and the remaining 1.7%(4/242)had other presenting symptoms.The AAO of motor was inversely correlated with the expanded CAG repeat length(R2=0.74,p<0.001).Analysis of 46 parent-child pairs showed that the CAG repeat length in the offspring group(45.8±7.6)was longer than in the parent group(43.8±3.0)(p=0.005),indicating the CAG in the parental transmittion was more unstable.Conclusion:This study provides clinical and genetic spectrum in a cohort of Chinese patients with HD,which contributes to a better understanding of this disease.Section Ⅱ:The HTT haplotype analysis in ChinaAim:To explore the haplotype characteristics in HD patients of Chinese origin and provide specific single nucleotide polymorphisms(SNPs)for allele-specific gene expression lowing treatment.Methods:A total of 406 individuals with expanded CAG repeats and 59 normal relatives,from 253 HD families,were enrolled between 2008 and 2018 from the neurologic clinics of three medical centers in Southeastern China.Twenty-nine SNPs were selected and genotyped for haplotype analysis.Results:In stage one,we used 18 tag SNPs(tSNPs)to construct haplogroups,confirming that the majority of HD patients in our cohort occurred predominantly on haplogroup variant A5(35.6%)and haplogroup C(45.5%),rarely on risk-associated haplogroup variant A1 and A2.In stage two,we selected 29 tSNPs to define new haplogroups(Ⅰ,Ⅱ,Ⅲ)and found haplogroup I accounting for 61.4%of HD chromosomes while 34.4%on control chromosomes.This difference was caused by haplogroup variant I-1,which was 20.2%on HD chromosome and 4.7%on control chromosomes.Furthermore,we identified rs2530596 that could cover theoretically 56.1%of HD patients of Chinese population for allele-specific gene expression lowering therapy.Conclusion:To our best knowledge,this is the first haplotype analysis encompassing HTT gene of Chinese descent,which provides candidate SNPs for gene therapy.