Yau Wai Yan, Sullivan Roisin, O'Connor Emer, Pellerin David, Parkinson Michael H, Giunti Paola, Dicaire Marie-Josée, Danzi Matt C, Züchner Stephan, Brais Bernard, Wood Nicholas W, Houlden Henry, Vandrovcova Jana
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, United Kingdom.
Perron Institute for Neurological and Translational Science, the University of Western Australia, Nedlands, Western Australia 6009, Australia.
Brain Commun. 2025 May 17;7(3):fcaf188. doi: 10.1093/braincomms/fcaf188. eCollection 2025.
Less than half of the individuals with hereditary cerebellar ataxia receives a genetic diagnosis. Repeat expansions account for disproportionate number of hereditary cerebellar ataxia and have genetically heterogeneous causes. These genetic loci include , , , , , , , , , and This study aims to assess the yield of short-read whole genome sequencing in the molecular diagnosis of hereditary cerebellar ataxia. We recruited 380 patients (351 probands) from a national ataxia centre in United Kingdom. They underwent short-read whole genome sequencing as a part of the 100 000 Genomes Project. Bioinformatic pipeline of whole genome sequencing include variant prioritization in selected virtual gene panels, customized analysis with a focus on repeat expansions, structural variants and recently reported hereditary cerebellar ataxia genes. All potential genetic variants were reviewed in a multidisciplinary team, and further confirmation tests were performed as appropriate. Whole genome sequencing identified causative variants in 115 (33%) out of 351 probands. We established 46 distinct presumptive molecular diagnoses with the most frequent being ( = 22) ( = 20) and ( = 10). However, it failed to detect any probands with novel ataxia gene , which was subsequently identified on polymerase chain reaction screening in 10 unsolved probands. In conclusion, whole genome sequencing is a useful diagnostic test in hereditary cerebellar ataxia patients and can be used to detect repeat expansions, structural and mitochondrial variants. However, identification of complex structural variants and sizing of large repeat expansions remains a challenge and require alternative molecular testing techniques.
遗传性小脑共济失调患者中不到一半能获得基因诊断。重复序列扩增在遗传性小脑共济失调中占比过高，且具有基因异质性病因。这些基因位点包括……本研究旨在评估短读长全基因组测序在遗传性小脑共济失调分子诊断中的诊断率。我们从英国一个全国性共济失调中心招募了380名患者（351名先证者）。他们接受了短读长全基因组测序，作为“10万基因组计划”的一部分。全基因组测序的生物信息学流程包括在选定的虚拟基因 panel 中对变异进行优先级排序、以重复序列扩增、结构变异和最近报道的遗传性小脑共济失调相关基因为重点的定制分析。所有潜在的基因变异都在一个多学科团队中进行了审查，并在适当的时候进行了进一步的确认测试。全基因组测序在351名先证者中的115名（33%）中鉴定出了致病变异。我们建立了46种不同的推定分子诊断，其中最常见的是……然而，它未能检测到任何携带新的共济失调基因……的先证者，该基因随后在10名未解决的先证者的聚合酶链反应筛查中被鉴定出来。总之，全基因组测序是遗传性小脑共济失调患者中一种有用的诊断测试，可用于检测重复序列扩增、结构和线粒体变异。然而，复杂结构变异的鉴定和大重复序列扩增的大小测定仍然是一个挑战，需要替代的分子检测技术。 （原文中部分基因位点等表述未完整给出，翻译时保留原文形式）
