Department of Genetics, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.
Department of Artificial Intelligence, University of Groningen, 9700 AK Groningen, The Netherlands.
Int J Mol Sci. 2024 Oct 18;25(20):11205. doi: 10.3390/ijms252011205.
Currently, routine diagnostics for spinocerebellar ataxia (SCA) look for polyQ repeat expansions and conventional variations affecting the proteins encoded by known SCA genes. However, ~40% of the patients still remain without a genetic diagnosis after routine tests. Increasing evidence suggests that variations in the enhancer regions of genes involved in neurodegenerative disorders can also cause disease. Since the enhancers of SCA genes are not yet known, it remains to be determined whether variations in these regions are a cause of SCA. In this pilot project, we aimed to identify the enhancers of the SCA genes , , and in the human cerebellum using 4C-seq, publicly available datasets, reciprocal 4C-seq, and luciferase assays. We then screened these enhancers for copy number variants (CNVs) in a cohort of genetically undiagnosed SCA patients. We identified two active enhancers for each of the four SCA genes. CNV analysis did not reveal any CNVs in the enhancers of the four SCA genes in the genetically undiagnosed SCA patients. However, in one patient, we noted a CNV deletion with an unknown clinical significance near one of the enhancers. These results not only reveal elements involved in SCA gene regulation but can also lead to the discovery of novel SCA-causing genetic variants. As enhancer variations are being increasingly recognized as a cause of brain disorders, screening the enhancers of , , and for variations other than CNVs and identifying and screening enhancers of other SCA genes might elucidate the genetic cause in undiagnosed patients.
目前，脊髓小脑共济失调（SCA）的常规诊断方法是寻找多聚 Q 重复扩展和影响已知 SCA 基因编码蛋白的常规变异。然而，在常规检查后，仍有约 40%的患者没有得到基因诊断。越来越多的证据表明，参与神经退行性疾病的基因增强子区域的变异也可能导致疾病。由于 SCA 基因的增强子尚不清楚，因此仍需确定这些区域的变异是否是 SCA 的原因。在这个试点项目中，我们旨在使用 4C-seq、公开可用的数据集、相互 4C-seq 和荧光素酶测定法，鉴定人类小脑中的 SCA 基因、、和的增强子。然后，我们在一组遗传上未诊断的 SCA 患者中筛选这些增强子的拷贝数变异（CNV）。我们为四个 SCA 基因中的每一个鉴定了两个活性增强子。CNV 分析未在遗传上未诊断的 SCA 患者的四个 SCA 基因的增强子中发现任何 CNV。然而，在一位患者中，我们注意到一个增强子附近的 CNV 缺失，其临床意义未知。这些结果不仅揭示了参与 SCA 基因调控的元件，还可能导致发现新的 SCA 致病遗传变异。由于增强子变异越来越被认为是导致大脑疾病的原因，因此筛选、、和的增强子的除 CNV 以外的变异，并鉴定和筛选其他 SCA 基因的增强子，可能会阐明未诊断患者的遗传原因。
