Department of Neurology, National Neuroscience Institute, Singapore, Singapore.
Neuroscience and Behavioural Disorders Programme, Duke-NUS Medical School, Singapore, Singapore.
Mov Disord. 2024 Oct;39(10):1829-1842. doi: 10.1002/mds.29932. Epub 2024 Aug 16.
Progressive supranuclear palsy (PSP) is largely a sporadic disease with few reported familial cases. Genome-wide association studies (GWAS) in sporadic PSP in Caucasian populations have identified MAPT as the most commonly associated genetic risk locus with the strongest effect size. At present there are limited data on genetic factors associated with PSP in Asian populations.
Our goal was to investigate the genetic factors associated with PSP in Southeast Asian PSP patients.
Next-generation sequencing (whole-exome, whole-genome and targeted sequencing) was performed in two Asian cohorts, comprising 177 PSP patients.
We identified 17 pathogenic or likely pathogenic variants in 16 PSP patients (9%), eight of which were novel. The most common relevant genetic variants identified were in MAPT, GBA1, OPTN, SYNJ1, and SQSTM1. Other variants detected were in TBK1, PRNP, and ABCA7-genes that have been implicated in other neurodegenerative diseases. Eighteen patients had a positive family history, of whom two carried pathogenic MAPT variants, and one carried a likely pathogenic GBA1 variant. None of the patients had expanded repeats in C9orf72. Furthermore, we found 16 different variants of uncertain significance in 21 PSP patients in PSEN2, ABCA7, SMPD1, MAPT, ATP13A2, OPTN, SQSTM1, CYLD, and BSN.
The genetic findings in our PSP cohorts appear to be somewhat distinct from those in Western populations, and also suggest an overlap of the genetic architecture between PSP and other neurodegenerative diseases. Further functional studies and validation in independent Asian cohorts will be useful for improving our understanding of PSP genetics and guiding genetic screening strategies in these populations. © 2024 International Parkinson and Movement Disorder Society.
进行性核上性麻痹（PSP）主要为散发性疾病，报道的家族病例较少。在白种人群的散发性 PSP 全基因组关联研究（GWAS）中，MAPT 被确定为与最强效应大小最相关的遗传风险基因座。目前，关于亚洲人群 PSP 相关遗传因素的资料有限。
我们的目标是研究东南亚 PSP 患者与 PSP 相关的遗传因素。
对两个亚洲队列（共 177 例 PSP 患者）进行了下一代测序（全外显子、全基因组和靶向测序）。
我们在 16 例 PSP 患者（9%）中发现了 17 种致病性或可能致病性的变异，其中 8 种为新发现的变异。最常见的相关遗传变异发生在 MAPT、GBA1、OPTN、SYNJ1 和 SQSTM1 基因中。还检测到 TBK1、PRNP 和 ABCA7 基因中的其他变异，这些基因与其他神经退行性疾病有关。18 例患者有阳性家族史，其中 2 例携带致病性 MAPT 变异，1 例携带可能致病性 GBA1 变异。无患者携带 C9orf72 扩增重复序列。此外，我们在 21 例 PSP 患者的 PSEN2、ABCA7、SMPD1、MAPT、ATP13A2、OPTN、SQSTM1、CYLD 和 BSN 基因中发现了 16 种不同的意义未明的变异。
我们 PSP 队列的遗传发现似乎与西方人群的发现有些不同，这也表明 PSP 与其他神经退行性疾病的遗传结构存在重叠。在独立的亚洲队列中进行进一步的功能研究和验证，将有助于我们更好地了解 PSP 的遗传学，并为这些人群的遗传筛查策略提供指导。© 2024 国际帕金森病和运动障碍学会。
