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Publication Detail
Comprehensive genetic diagnosis of tandem repeat expansion disorders with programmable targeted nanopore sequencing
  • Publication Type:
    Journal article
  • Authors:
    Stevanovski I, Chintalaphani SR, Gamaarachchi H, Ferguson JM, Pineda SS, Scriba CK, Tchan M, Fung V, Ng K, Cortese A, Houlden H, Dobson-Stone C, Fitzpatrick L, Halliday G, Ravenscroft G, Davis MR, Laing NG, Fellner A, Kennerson M, Kumar KR, Deveson IW
  • Publisher:
    American Association for the Advancement of Science (AAAS)
  • Publication date:
    04/03/2022
  • Journal:
    Science Advances
  • Volume:
    8
  • Issue:
    9
  • Article number:
    eabm5386
  • Medium:
    Print-Electronic
  • Status:
    Published
  • Country:
    United States
  • Language:
    English
  • Notes:
    © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S.Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
Abstract
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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Department of Neuromuscular Diseases
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Department of Neuromuscular Diseases
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