PDF(Pubmed)
Abstract：
Spinocerebellar ataxia (SCA) is a heterogeneous group of neurodegenerative disorders with autosomal dominant inheritance. Genetic testing for SCA leads to diagnosis, prognosis and risk assessment for patients and their family members. While advances in sequencing and computing technologies have provided researchers with a rapid expansion in the genetic test content that can be used to unravel the genetic causes that underlie diseases, the large number of variants with unknown significance (VUSes) detected represent challenges. To minimize the proportion of VUSes, follow-up studies are needed to aid in their reclassification as either (likely) pathogenic or (likely) benign variants. In this study, we addressed the challenge of prioritizing VUSes for follow-up using (a combination of) variant segregation studies, 3D protein modeling, in vitro splicing assays and functional assays. Of the 39 VUSes prioritized for further analysis, 13 were eligible for follow up. We were able to reclassify 4 of these VUSes to LP, increasing the molecular diagnostic yield by 1.1%. Reclassification of VUSes remains difficult due to limited possibilities for performing variant segregation studies in the classification process and the limited availability of routine functional tests.
摘要：
脊髓小脑共济失调（SCA）是一组具有常染色体显性遗传的神经退行性疾病。SCA的基因检测导致诊断，患者及其家庭成员的预后和风险评估。虽然测序和计算技术的进步为研究人员提供了基因测试内容的快速扩展，可用于揭示疾病背后的遗传原因，检测到的大量意义未知的变异(VUSes)代表挑战.为了最小化VUSE的比例，需要进行后续研究,以帮助将其重新分类为(可能的)致病性变异或(可能的)良性变异.在这项研究中,我们解决了使用（组合）变异分离研究将VUSes优先进行随访的挑战，三维蛋白质建模,体外剪接测定和功能测定。在优先进行进一步分析的39个车辆中，13人符合随访条件。我们能够将这些VUSE中的4个重新分类为LP，将分子诊断产量提高1.1%。由于在分类过程中进行变体分离研究的可能性有限以及常规功能测试的可用性有限，VUSes的重新分类仍然很困难。
