Comprehensive genetic diagnosis of tandem repeat expansion disorders with programmable targeted nanopore sequencing-Reference-Cited by-同舟云学术

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

Published:2022-03-04 Issue:9 Volume:8 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Stevanovski Igor¹^ORCID,Chintalaphani Sanjog R.¹²³^ORCID,Gamaarachchi Hasindu¹⁴^ORCID,Ferguson James M.¹^ORCID,Pineda Sandy S.⁵⁶^ORCID,Scriba Carolin K.⁷⁸,Tchan Michel⁹^ORCID,Fung Victor⁹^ORCID,Ng Karl¹⁰^ORCID,Cortese Andrea¹¹¹²,Houlden Henry¹¹¹²^ORCID,Dobson-Stone Carol⁶^ORCID,Fitzpatrick Lauren⁶,Halliday Glenda⁶^ORCID,Ravenscroft Gianina⁷,Davis Mark R.⁷^ORCID,Laing Nigel G.⁷⁸^ORCID,Fellner Avi¹¹³¹⁴^ORCID,Kennerson Marina¹⁵¹⁶¹⁷^ORCID,Kumar Kishore R.¹¹⁷¹⁸^ORCID,Deveson Ira W.¹³^ORCID

Affiliation:

1. Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia.

2. School of Medicine, University of New South Wales, Sydney, NSW, Australia.

3. St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.

4. School of Computer Science and Engineering, University of New South Wales, Sydney, NSW, Australia.

5. Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia.

6. The University of Sydney, Brain and Mind Centre and School of Medical Sciences, Faculty of Medicine and Health, Camperdown, NSW, Australia.

7. Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, WA, Australia.

8. Diagnostic Genomics, PathWest Laboratory Medicine WA, Nedlands, WA, Australia.

9. Westmead Hospital, Westmead, NSW, Australia and Sydney Medical School, The University of Sydney, NSW, Australia.

10. Department of Neurology, Royal North Shore Hospital and The University of Sydney, Sydney, NSW, Australia.

11. Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.

12. The National Hospital for Neurology and Neurosurgery, London, UK.

13. Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel.

14. The Neurology Department, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel.

15. Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, NSW, Australia.

16. Faculty of Health and Medicine, University of Sydney, Camperdown, NSW, Australia.

17. Molecular Medicine Laboratory, Concord Hospital, Concord, NSW, Australia.

18. Neurology Department, Central Clinical School, Concord Repatriation General Hospital, University of Sydney, Concord, NSW, Australia.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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