Variation in tandem repeats (TRs), particularly large expansions of triplet repeats (e.g., polyCAG), is known to cause a number of late-onset neurological diseases. Due to their repetitive and degenerate nature, variation in TRs is typically not captured by standard genome analysis pipelines. Furthermore, pathogenic repeat expansions can span hundreds to thousands of bases, making them difficult to detect using short-read sequencing data.

However, specialized algorithms have been developed that enable short tandem repeats (STRs; motif sizes of 1–20 bp) to be genotyped from short-read sequencing data, including expanded alleles whose sizes exceed the read length. ExpansionHunter Denovo was first used to screen the ADSP R4 whole-genome sequencing data for expanded STR alleles. These results were then combined with analyses of other diverse genomes to create a custom catalog of approximately 165,000 STRs, representing tandem repeats in the human genome that show high levels of polymorphism and/or a high propensity to undergo rare expansions. These STRs were subsequently genotyped in the ADSP R4 whole-genome sequencing samples using ExpansionHunter.