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Enhanced mitochondrial genome analysis: bioinformatic and long-read sequencing advances and their diagnostic implications

Macken, WL; Falabella, M; Pizzamiglio, C; Woodward, CE; Scotchman, E; Chitty, LS; Polke, JM; ... Pitceathly, RDS; + view all (2023) Enhanced mitochondrial genome analysis: bioinformatic and long-read sequencing advances and their diagnostic implications. Expert Review of Molecular Diagnostics , 23 (9) pp. 797-814. 10.1080/14737159.2023.2241365. Green open access

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Abstract

Introduction: Primary mitochondrial diseases (PMDs) comprise a large and heterogeneous group of genetic diseases that result from pathogenic variants in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). Widespread adoption of next-generation sequencing (NGS) has improved the efficiency and accuracy of mtDNA diagnoses; however, several challenges remain. Areas covered: In this review, we briefly summarize the current state of the art in molecular diagnostics for mtDNA and consider the implications of improved whole genome sequencing (WGS), bioinformatic techniques, and the adoption of long-read sequencing, for PMD diagnostics. Expert opinion: We anticipate that the application of PCR-free WGS from blood DNA will increase in diagnostic laboratories, while for adults with myopathic presentations, WGS from muscle DNA may become more widespread. Improved bioinformatic strategies will enhance WGS data interrogation, with more accurate delineation of mtDNA and NUMTs (nuclear mitochondrial DNA segments) in WGS data, superior coverage uniformity, indirect measurement of mtDNA copy number, and more accurate interpretation of heteroplasmic large-scale rearrangements (LSRs). Separately, the adoption of diagnostic long-read sequencing could offer greater resolution of complex LSRs and the opportunity to phase heteroplasmic variants.

Type: Article
Title: Enhanced mitochondrial genome analysis: bioinformatic and long-read sequencing advances and their diagnostic implications
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1080/14737159.2023.2241365
Publisher version: https://doi.org/10.1080/14737159.2023.2241365
Language: English
Additional information: © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
Keywords: Bioinformatics, large-scale rearrangements, long-read sequencing, mitochondrial DNA, primary mitochondrial diseases
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10176202
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