Use of whole-genome sequencing for mitochondrial disease diagnosis

Ryan L. Davis, Kishore R. Kumar, Clare Puttick, Christina Liang, Kate E. Ahmad, Fabienne Edema-Hildebrand, Jin-Sung Park, Andre E. Minoche, Velimir Gayevskiy, Amali C. Mallawaarachchi, John Christodoulou, Deborah Schofield, Marcel E. Dinger, Mark J. Cowley, Carolyn M Sue

    Research output: Contribution to journalArticlepeer-review

    16 Citations (Scopus)
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    Background and Objectives: Mitochondrial diseases (MDs) are the commonest group of heritable metabolic disorders. Phenotypic diversity can make molecular diagnosis challenging, and causative genetic variants may reside in either mitochondrial or nuclear DNA. A single comprehensive genetic diagnostic test would be highly useful and transform the field. We applied whole-genome sequencing (WGS) to evaluate the variant detection rate and diagnostic capacity of this technology with a view to simplifying and improving the MD diagnostic pathway.

    Methods: Adult patients presenting to a specialist MD clinic in Sydney, Australia, were recruited to the study if they satisfied clinical MD (Nijmegen) criteria. WGS was performed on blood DNA, followed by clinical genetic analysis for known pathogenic MD-associated variants and MD mimics.

    Results: Of the 242 consecutive patients recruited, 62 participants had “definite,” 108 had “probable,” and 72 had “possible” MD classification by the Nijmegen criteria. Disease-causing variants were identified for 130 participants, regardless of the location of the causative genetic variants, giving an overall diagnostic rate of 53.7% (130 of 242). Identification of causative genetic variants informed precise treatment, restored reproductive confidence, and optimized clinical management of MD.

    Discussion: Comprehensive bigenomic sequencing accurately detects causative genetic variants in affected MD patients, simplifying diagnosis, enabling early treatment, and informing the risk of genetic transmission.

    Original languageEnglish
    Pages (from-to)e730-e742
    Number of pages13
    Issue number7
    Early online date31 May 2022
    Publication statusPublished - 16 Aug 2022

    Bibliographical note

    Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.


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