The autosomal dominant cerebellar ataxias, referred to as spinocerebellar ataxias in genetic nomenclature, are a rare group of progressive neurodegenerative disorders characterized by loss of balance and coordination. Despite the identification of numerous disease genes, a substantial number of cases still remain without a genetic diagnosis. Here, we report five novel spinocerebellar ataxia genes, FAT2, PLD3, KIF26B, EP300, and FAT1, identified through a combination of exome sequencing in genetically undiagnosed families and targeted resequencing of exome candidates in a cohort of singletons. We validated almost all genes genetically, assessed damaging effects of the gene variants in cell models and further consolidated a role for several of these genes in the aetiology of spinocerebellar ataxia through network analysis. Our work links spinocerebellar ataxia to alterations in synaptic transmission and transcription regulation, and identifies these as the main shared mechanisms underlying the genetically diverse spinocerebellar ataxia types.

中文翻译：

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外显子组测序和网络分析确定了脊髓小脑共济失调的共同机制

常染色体显性遗传性小脑性共济失调，在遗传术语中称为脊髓小脑性共济失调，是一种罕见的进行性神经退行性疾病，其特征是失去平衡和协调性。尽管鉴定了许多疾病基因，但仍有大量病例没有遗传学诊断。在这里，我们报告五个新颖的小脑共济失调基因，FAT2，PLD3，KIF26B，EP300和FAT1，是通过将遗传未诊断的家族中的外显子组测序与一组单身人群中的外显子组候选物有针对性地重新测序相结合而确定的。我们通过遗传方法验证了几乎所有基因，评估了细胞模型中基因变异的破坏作用，并通过网络分析进一步巩固了这些基因中的几个在脊髓小脑共济失调病因中的作用。我们的工作将脊髓小脑性共济失调与突触传递和转录调控的改变联系起来，并将这些识别为遗传上多样化的脊髓小脑性共济失调类型的主要共享机制。