Comprehensive genetic diagnosis of tandem repeat expansion disorders with programmable targeted nanopore sequencing

Igor Stevanovski, Sanjog R. Chintalaphani, Hasindu Gamaarachchi, James M. Ferguson, Sandy S. Pineda, Carolin K. Scriba, Michel Tchan, Victor Fung, Karl Ng, Andrea Cortese, Henry Houlden, Carol Dobson-Stone, Lauren Fitzpatrick, Glenda Halliday, Gianina Ravenscroft, Mark R. Davis, Nigel G. Laing, Avi Fellner, Marina Kennerson, Kishore R. KumarIra W. Deveson

Research output: Contribution to journalArticlepeer-review

58 Citations (Scopus)

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.

Original languageEnglish
Article numbereabm5386
JournalScience Advances
Volume8
Issue number9
DOIs
Publication statusPublished - Mar 2022

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