Watanabe Tomoaki, Kume Kodai, Inoue Ken, Nakamura Masataka, Yamamoto Shinji, Kurashige Takashi, Ohshita Tomohiko, Tazuma Taku, Kaido Misako, Maetani Yuta, Maruyama Hirofumi, Kawakami Hideshi
Department of Molecular Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
Department of Clinical Neuroscience and Therapeutics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
J Hum Genet. 2025 Sep 12. doi: 10.1038/s10038-025-01405-2.
Spinocerebellar degeneration (SCD) is a clinically and genetically diverse group, and the dominant form of SCD (AD-SCD) is generally referred to as spinocerebellar ataxia (SCA) that primarily affects the cerebellum. Some patients do not have a definitive genetic diagnosis but may carry unknown variants of known causative genes. Here, we screened for known SCA-associated genes in patients with suspected SCA. We examined 174 patients with SCA lacking abnormal repeat expansion of known causative genes. Whole-exome sequencing (WES) was performed to screen for variants in SCA-associated genes. The identified variants were confirmed by Sanger sequencing, and their pathogenicity was determined using five web-based algorithms. WES revealed novel single-nucleotide variants (SNVs) in three genes, ELOVL4, ELOVL5, and GRM1. Patients presented with symptoms other than cerebellar symptoms. One patient with an ELOVL4 variant exhibited skin changes, a typical symptom of ELOVL4 SCA, whereas the other ELOVL4 SCA patient had no skin changes and exhibited mild parkinsonism and calcification in the globus pallidus and dentate nucleus. The patient with an ELOVL5 variant exhibited bladder and rectal disturbances. Finally, patients with GRM1 variants showed few common features beyond the cerebellar symptoms. One patient showed white matter lesions, cognitive decline, and no-no head tremors, whereas the other showed spasticity. The identification of novel SNVs in these known SCA-associated genes will expand our understanding of the genetic landscape of SCA and facilitate the diagnosis of previously undiagnosed patients.
脊髓小脑变性（SCD）是一个临床和遗传异质性的群体，SCD的主要形式（常染色体显性脊髓小脑变性，AD-SCD）通常被称为脊髓小脑共济失调（SCA），主要影响小脑。一些患者没有明确的基因诊断，但可能携带已知致病基因的未知变异。在这里，我们对疑似SCA患者进行了已知SCA相关基因的筛查。我们检查了174例缺乏已知致病基因异常重复扩增的SCA患者。进行全外显子组测序（WES）以筛查SCA相关基因中的变异。通过桑格测序确认所鉴定的变异，并使用五种基于网络的算法确定其致病性。WES在三个基因ELOVL4、ELOVL5和GRM1中发现了新的单核苷酸变异（SNV）。患者表现出除小脑症状以外的症状。一名携带ELOVL4变异的患者出现皮肤改变，这是ELOVL4型SCA的典型症状，而另一名ELOVL4型SCA患者没有皮肤改变，表现出轻度帕金森症以及苍白球和齿状核钙化。携带ELOVL5变异的患者出现膀胱和直肠功能障碍。最后，携带GRM1变异的患者除小脑症状外几乎没有共同特征。一名患者出现白质病变、认知衰退和点头震颤，而另一名患者表现为痉挛。在这些已知SCA相关基因中鉴定出新的SNV将扩展我们对SCA遗传图谱的理解，并有助于诊断以前未确诊的患者。
