ABSTRACT
BACKGROUND: Knowledge of the genetic background of many human diseases is currently lacking from genetically undiscovered regions, including Central Asia. Kazakhstan is the first Central Asian country where the genetic studies of Parkinson's disease (PD) have been emerging since it had become a member of the International Parkinson Disease Genomics Consortium. Here we report on the results of whole-exome sequencing (WES) in 50 young-onset PD (YOPD) cases from Kazakhstan. METHODOLOGY: WES was performed on 50 unrelated individuals with YOPD from Kazakhstan. Exome data were screened for novel/ultra-rare deleterious variants in known and candidate PD genes. Copy number variants and small indels were also called. RESULTS: Only three cases (6%) were found to be positive for known PD genes including two unrelated familial PD cases with LRRK2 p.(Arg1441Cys) and one case with a homozygous pathogenic PRKN p.(Arg84Trp) variant. Four cases had novel and ultra-rare variants of uncertain significance in LRRK2, DNAJC13, and VPS35. Novel deleterious variants were found in candidate Mendelian PD genes including CSMD1, TNR, EIF4G1, and ATP13A3. Eight cases harbored the East Asian-specific LRRK2 p.(Ala419Val) variant. CONCLUSIONS: The low diagnostic yield in our study might imply that a significant proportion of YOPD cases in Central Asia remains unresolved. Therefore, a better understanding of the genetic architecture of PD among populations of Central Asian ancestry and the pathogenicity of numerous rare variants should be further investigated. WES is a valuable technique for large-scale YOPD genetic studies in Central Asia.
Subject(s)
Gene Frequency , Genetic Heterogeneity , Parkinson Disease/genetics , Adenosine Triphosphatases/genetics , Adolescent , Adult , Age of Onset , Eukaryotic Initiation Factor-4G/genetics , Female , Humans , Kazakhstan , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics , Male , Membrane Proteins/genetics , Membrane Transport Proteins/genetics , Middle Aged , Molecular Chaperones/genetics , Parkinson Disease/pathology , Tenascin/genetics , Tumor Suppressor Proteins/geneticsSubject(s)
Antiparkinson Agents/administration & dosage , Levodopa/administration & dosage , Parkinson Disease/drug therapy , Parkinson Disease/epidemiology , Adolescent , Adult , Age of Onset , Aged , Aged, 80 and over , Disease Progression , Female , Humans , Kazakhstan/epidemiology , Male , Middle Aged , Parkinson Disease/classification , Parkinson Disease/physiopathology , Retrospective Studies , Sex Factors , Young AdultABSTRACT
BACKGROUND: LRRK2 mutations have emerged as the most prevalent and potentially treatable determinants of Parkinson's disease (PD). Peculiar geographic distribution of these mutations has triggered an interest in genotyping PD cohorts of different ethnic backgrounds for LRRK. OBJECTIVE: Here, we report on the results of LRRK2 screening in the first Central Asian PD cohort. METHODS: 246 PD patients were consecutively recruited by movement disorder specialists from four medical centers in Kazakhstan, and clinicodemographic data and genomic DNA from blood were systematically obtained and shipped to the Institute of Neurology University College London together with DNAs from 200 healthy controls. The cohort was genotyped for five LRRK2 mutations (p.Gly2019Ser, p.Arg1441His, p.Tyr1699Cys, p.Ile2020Thr, and p.Asn1437His) and three East Asian disease-associated variants (p.Gly2385Arg, p.Ala419Val, and p.Arg1628Pro) via Kompetitive allele-specific polymerase chain reaction assay analysis. RESULTS: None of the study subjects carried LRRK2 mutations, whereas the following Asian variants were found with insignificant odds ratios (OR): p.Gly2385Arg (1.2%, minor allele frequency (MAF) 0.007, OR 1.25, p=0.8), p.Ala419Val (3.7%, MAF 0.02, OR 1.5, p=0.8), p.Ala419Val (3.7%, MAF 0.02, OR 1.5. CONCLUSIONS: We showed that East Asian LRRK variants could be found in Central Asian populations but their pathogenicity remains to be elucidated in larger PD cohorts.
