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.

对于短读全基因组测序（WGS）数据，鉴定短串联重复序列（STR）的大扩增，例如引起肌萎缩性侧索硬化（ALS）和脆性X综合征的那些扩增，是一项挑战。解决此问题的方法是将WGS集成到精密医学中的重要一步。我们开发了一个名为ExpansionHunter的软件工具，该工具使用无PCR的WGS短读数据，即使扩展的重复序列大于读取长度，也可以在感兴趣的基因座进行重复序列的基因分型。我们将算法应用于3001例经过C9orf72检测的ALS患者的WGS数据使用重复引物PCR（RP-PCR）进行重复扩增。与该真实数据相比，ExpansionHunter将所有扩展样本（212 / 212，95％CI [0.98，1.00]）正确分类为扩展（208）或潜在扩展（4）。此外，通过这种方法，将99.9％（2786/2789，95％CI [0.997，1.00]）的野生型样品正确分类为野生型，其余三个样品被确定为可能的扩增。我们进一步将算法应用于一组152个样本中，其中每个样本具有八个不同的病原体重复扩展中的一个，包括与脆弱X综合征，Friedreich共济失调和亨廷顿病相关的那些，并正确标记了除已知重复扩展之外的所有扩展。 。因此，