Identifying large expansions of short tandem repeats (STRs), such as those that cause amyotrophic lateral sclerosis (ALS) and fragile X syndrome, is challenging for short-read whole-genome sequencing (WGS) data. A solution to this problem is an important step toward integrating WGS into precision medicine. We developed a software tool called ExpansionHunter that, using PCR-free WGS short-read data, can genotype repeats at the locus of interest, even if the expanded repeat is larger than the read length. We applied our algorithm to WGS data from 3001 ALS patients who have been tested for the presence of the C9orf72 repeat expansion with repeat-primed PCR (RP-PCR). Compared against this truth data, ExpansionHunter correctly classified all (212/212, 95% CI [0.98, 1.00]) of the expanded samples as either expansions (208) or potential expansions (4). Additionally, 99.9% (2786/2789, 95% CI [0.997, 1.00]) of the wild-type samples were correctly classified as wild type by this method with the remaining three samples identified as possible expansions. We further applied our algorithm to a set of 152 samples in which every sample had one of eight different pathogenic repeat expansions, including those associated with fragile X syndrome, Friedreich's ataxia, and Huntington's disease, and correctly flagged all but one of the known repeat expansions. Thus, ExpansionHunter can be used to accurately detect known pathogenic repeat expansions and provides researchers with a tool that can be used to identify new pathogenic repeat expansions.

识别短串联重复序列 (STR) 的大量扩增，例如导致肌萎缩侧索硬化 (ALS) 和脆性 X 综合征的那些，对于短读长全基因组测序 (WGS) 数据具有挑战性。解决这个问题是将 WGS 整合到精准医学中的重要一步。我们开发了一个名为 ExpansionHunter 的软件工具，它使用无 PCR 的 WGS 短读长数据，可以对感兴趣的基因座处的重复序列进行基因分型，即使扩展的重复序列大于读取长度。我们将我们的算法应用于来自 3001 名 ALS 患者的 WGS 数据，这些患者已接受过C9orf72存在测试使用重复引物 PCR (RP-PCR) 进行重复扩增。与该真实数据相比，ExpansionHunter 正确地将所有 (212/212, 95% CI [0.98, 1.00]) 扩展样本分类为扩展 (208) 或潜在扩展 (4)。此外，99.9% (2786/2789, 95% CI [0.997, 1.00]) 的野生型样品通过该方法被正确分类为野生型，其余三个样品被确定为可能的扩增。我们进一步将我们的算法应用于一组 152 个样本，其中每个样本都有八种不同的致病性重复扩展之一，包括与脆性 X 综合征、弗里德赖希共济失调和亨廷顿病相关的那些，并正确标记了除一个已知重复扩展之外的所有重复扩展. 因此，