Department of Neuromuscular Disorders, Institute of Neurology, University College London, London, UK.
Department of Molecular Genetics, National Center for Biotechnology, Nur-Sultan, Kazakhstan.
Mol Genet Genomic Med. 2021 Jun;9(6):e1671. doi: 10.1002/mgg3.1671. Epub 2021 Apr 5.
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.
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.
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.
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.
目前，包括中亚在内的遗传未发现区域缺乏许多人类疾病的遗传背景知识。哈萨克斯坦是自加入国际帕金森病基因组学联盟以来，首个开展帕金森病（PD）遗传研究的中亚国家。在此，我们报告了对 50 例哈萨克斯坦早发性 PD（YOPD）病例进行全外显子组测序（WES）的结果。
对 50 例来自哈萨克斯坦的无血缘关系的 YOPD 个体进行了 WES。在外显子数据中筛选已知和候选 PD 基因中的新型/超罕见有害变异。还对拷贝数变异和小的插入缺失进行了检测。
仅发现 3 例（6%）为已知 PD 基因阳性，包括 2 例无血缘关系的家族性 PD 病例，其 LRRK2 基因 p.(Arg1441Cys)和 1 例 PRKN 基因纯合致病性 p.(Arg84Trp)变异。4 例在 LRRK2、DNAJC13 和 VPS35 中发现新型和超罕见意义不明的变异。在候选孟德尔 PD 基因中发现了新型有害变异，包括 CSMD1、TNR、EIF4G1 和 ATP13A3。8 例携带东亚特异性 LRRK2 p.(Ala419Val)变异。
本研究中的低诊断率可能意味着中亚地区相当一部分 YOPD 病例仍未得到解决。因此，需要进一步了解中亚人群 PD 的遗传结构以及大量罕见变异的致病性。WES 是中亚地区大规模 YOPD 遗传研究的一种有价值的技术。
