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.