Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
Department of Neurology, Xiangya Hospital, Central South University, Changsha, China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
Parkinsonism Relat Disord. 2021 Aug;89:120-127. doi: 10.1016/j.parkreldis.2021.07.010. Epub 2021 Jul 10.
Hereditary ataxias demonstrate a high degree of clinical and genetic heterogeneity. Understanding the genetic etiology of hereditary ataxias is crucial for genetic counseling and clinical management.
The clinical and genetic data of patients with familial or sporadic ataxias who referred to our tertiary medical center were retrospectively analyzed. Probands in this study underwent SCA repeat expansion panel firstly to screen for repeat expansion SCAs; those with negative results had NGS-targeted panels or WES testing to detect conventional mutations.
A total of 223 patients were enrolled from 206 families. 5 kinds of coexisting SCA repeat expansions were observed (SCA3/SCA17, SCA3/SCA8, SCA2/SCA8, SCA3/SCA12 and SCA8/SCA12) in 12 patients from 8 families, among which SCA2/SCA8, SCA8/SCA12 and SCA3/SCA12 were reported for the first time. The coexistence of expanded SCA3 with SCA17 alleles was the most common in our study. NGS identified pathogenic/likely pathogenic variants in 12 ataxia causative genes in 13 probands. Spastic paraplegia ataxia was the most common diagnosis. Six novel mutations were detected in five ataxia-related genes.
Coexistence may not specific to a certain SCA subtype and the frequency might have been underestimated before. SCA repeat expansion panel should be considered in patients with overlapping SCA features. In addition, our study broadened the conventional mutation spectrum in ataxia-related genes. These results facilitate a better understanding of the genetic basis for hereditary ataxias.
遗传性共济失调表现出高度的临床和遗传异质性。了解遗传性共济失调的遗传病因对于遗传咨询和临床管理至关重要。
回顾性分析了就诊于我们三级医学中心的家族性或散发性共济失调患者的临床和遗传数据。本研究中的先证者首先进行 SCA 重复扩展面板检测，以筛查重复扩展 SCA；结果阴性者进行 NGS 靶向面板或 WES 检测以检测常规突变。
共纳入 223 名来自 206 个家系的患者。在 8 个家系的 12 名患者中观察到 5 种共存的 SCA 重复扩展（SCA3/SCA17、SCA3/SCA8、SCA2/SCA8、SCA3/SCA12 和 SCA8/SCA12），其中 SCA2/SCA8、SCA8/SCA12 和 SCA3/SCA12 为首次报道。在我们的研究中，扩展 SCA3 与 SCA17 等位基因的共存最为常见。NGS 在 13 名先证者的 12 个共济失调致病基因中鉴定出致病性/可能致病性变异。痉挛性截瘫共济失调是最常见的诊断。在五个与共济失调相关的基因中检测到六个新的突变。
共存可能不限于特定的 SCA 亚型，并且在以前可能被低估。在具有重叠 SCA 特征的患者中应考虑 SCA 重复扩展面板。此外，我们的研究拓宽了与共济失调相关基因的常规突变谱。这些结果有助于更好地理解遗传性共济失调的遗传基础。
