The Stacey Motor Neuron Disease Laboratory, Department of Pathology, Sydney Medical School, The University of Sydney, Australia.
J Neurosci Methods. 2011 Apr 30;197(2):297-301. doi: 10.1016/j.jneumeth.2011.02.028. Epub 2011 Mar 15.
Rare de novo genetic variants have been detected in a number of diseases using case-parent trios. So far, trio studies have largely been confined to early-onset diseases where parent DNA samples are readily available. To test the feasibility of finding rare de novo variants in a typical late-onset neurodegenerative disease, we compared genome-wide copy number variants (CNVs) between patients with sporadic amyotrophic lateral sclerosis (SALS) and their unaffected parents. DNA from 12 SALS patients and their 24 parents was analysed for CNVs using AffyMetrix SNP 6.0 microarrays and Partek software. De novo CNVs (present in patients but not their parents) considered likely candidates for SALS were those that overlapped with CNS-related genes, were rare, or were found in multiple patients. All SALS patients had de novo CNVs. In 11 patients, 37 de novo CNVs fulfilled one or more criteria for a candidate region. Eleven de novo CNVs overlapped with genes, some of which are in pathways suspected in the pathogenesis of SALS. In conclusion, this pilot study shows that trios can be used to look for rare de novo genetic variants in patients with late adult-onset neurodegenerative disease. The results suggest that further studies of this nature with larger numbers of trios are warranted, but it is unusual to find surviving parents of offspring who have a late-onset neurodegenerative disease. An international collaborative effort will therefore be needed to collect sufficient numbers of such trios to reliably detect de novo mutations underlying these diseases.
使用病例-父母三体型，已经在一些疾病中检测到了一些罕见的新生遗传变异。到目前为止，三体型研究主要局限于那些早期发病且父母 DNA 样本容易获得的疾病。为了测试在典型的晚发性神经退行性疾病中发现罕见新生变异的可行性，我们比较了散发性肌萎缩侧索硬化症（SALS）患者与其未受影响的父母之间的全基因组拷贝数变异（CNVs）。使用 AffyMetrix SNP 6.0 微阵列和 Partek 软件，对 12 名 SALS 患者及其 24 名父母的 DNA 进行了 CNV 分析。新生 CNVs（仅存在于患者中而不存在于其父母中）被认为是 SALS 的可能候选者，包括与中枢神经系统相关的基因重叠、罕见或在多个患者中发现的 CNVs。所有 SALS 患者均存在新生 CNVs。在 11 名患者中，有 37 个新生 CNV 符合候选区域的一个或多个标准。11 个新生 CNVs 与基因重叠，其中一些基因与 SALS 发病机制中的疑似途径有关。总之，这项初步研究表明，三体型可用于寻找晚发性成年神经退行性疾病患者中罕见的新生遗传变异。结果表明，需要进一步进行更大规模的三体型研究，但找到患有晚发性神经退行性疾病的子女的幸存父母并不常见。因此，需要开展国际合作，收集足够数量的三体型，以可靠地检测这些疾病的新生突变。
