Journal
SCIENCE ADVANCES
Volume 8, Issue 9, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abm5386
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Funding
- Australian Medical Research Futures Fund (MRFF) Investigator grant [MRF1173594]
- Australian National Health and Medical Research Council (NHMRC) [APP1122952, APP1117510]
- Australian Government Research Training Program (RTP) Scholarship
- Kinghorn Foundation
- Margaret and Terry Orr Memorial Fund
- Paul Ainsworth Family Foundation
- Michael J. Fox Foundation, Aligning Science Across Parkinson's (ASAP) initiative
- MRFF Genomics Future Health Missions grant [2007681]
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This article describes a method for genotyping neurological STR expansions using targeted long-read sequencing with Oxford Nanopore's ReadUntil function. The method allows for accurate DNA analysis and haplotype-resolved assembly, and successfully diagnoses patients with neurogenetic diseases. Long-read sequencing solves large and complex STR expansions and reveals a diversity of STR alleles.
More than 50 neurological and neuromuscular diseases are caused by short tandem repeat (STR) expansions, with 37 different genes implicated to date. 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 assay. Our approach enables accurate, haplotype-resolved assembly and DNA methylation profiling of STR sites, from a list of predetermined candidates. This correctly diagnoses all individuals in a small cohort (n = 37) including patients with various neurogenetic diseases (n = 25). Targeted long-read sequencing solves large and complex STR expansions that confound established molecular tests and short-read sequencing and identifies noncanonical STR motif conformations and internal sequence interruptions. We observe a diversity of STR alleles of known and unknown pathogenicity, suggesting that long-read sequencing will redefine the genetic landscape of repeat disorders. Last, we show how the inclusion of pharmacogenomic genes as secondary ReadUntil targets can further inform patient care.
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