Short-tandem repeat (STR) expansions are an important class of pathogenic genetic variants. Over forty neurological and neuromuscular diseases are caused by STR expansions, with 37 different genes implicated to date. Here we describe the use of programmable targeted long-read sequencing with Oxford Nanopore’s ReadUntil function for parallel genotyping of all known neuropathogenic STRs in a single, simple assay. Our approach enables accurate, haplotype-resolved assembly and DNA methylation profiling of expanded and non-expanded STR sites. In doing so, the assay correctly diagnoses all individuals in a cohort of patients (n = 27) with various neurogenetic diseases, including Huntington’s disease, fragile X syndrome and cerebellar ataxia (CANVAS) and others. Even in our relatively small cohort, we observe a wide diversity of STR alleles of known and unknown pathogenicity, suggesting that long-read sequencing will redefine the genetic landscape of STR expansion disorders.
Pre-print available: https://www.medrxiv.org/content/10.1101/2021.09.27.21263187v1