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August 16, 2022; 99 (7) Research ArticlesOpen Access

Use of Whole-Genome Sequencing for Mitochondrial Disease Diagnosis

View ORCID ProfileRyan L. Davis, View ORCID ProfileKishore R. Kumar, Clare Puttick, View ORCID ProfileChristina Liang, Kate E. Ahmad, Fabienne Edema-Hildebrand, Jin-Sung Park, Andre E. Minoche, Velimir Gayevskiy, View ORCID ProfileAmali C. Mallawaarachchi, View ORCID ProfileJohn Christodoulou, View ORCID ProfileDeborah Schofield, View ORCID ProfileMarcel E. Dinger, View ORCID ProfileMark J. Cowley, View ORCID ProfileCarolyn M. Sue
First published May 31, 2022, DOI: https://doi.org/10.1212/WNL.0000000000200745
Ryan L. Davis
From the Department of Neurogenetics (R.L.D., K.R.K., C.L., K.E.A., F.E.-H., J.-S.P., C.M.S.), Kolling Institute, Faculty of Medicine and Health, University of Sydney and Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Kinghorn Centre for Clinical Genomics (R.L.D., K.R.K., C.P., A.E.M., V.G., A.C.M., M.E.D., M.J.C., C.M.S.), Garvan Institute of Medical Research, Darlinghurst; Department of Neurology (K.R.K., C.L., K.E.A., F.E.-H., C.M.S.), Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Dr. Kumar is now with Molecular Medicine Laboratory, Concord Hospital, Concord, New South Wales, Australia; Dr. Park is now with Cenyx Biotech, Jongno-gu, Seoul, South Korea; Brain and Mitochondrial Research Group (J.C.), Murdoch Children's Research Institute, Parkville, Melbourne; Department of Paediatrics (J.C.), University of Melbourne, Victoria; Prof. Schofield is now with GenIMPACT: Centre for Economic Impacts of Genomic Medicine, Macquarie University, Macquarie Park; Prof. Dinger is now with School of Biotechnology and Biomolecular Sciences, University of New South Wales, Randwick; and Prof. Cowley is now with Computational Biology Group, Children's Cancer Institute, University of New South Wales, Randwick, Australia.
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Kishore R. Kumar
From the Department of Neurogenetics (R.L.D., K.R.K., C.L., K.E.A., F.E.-H., J.-S.P., C.M.S.), Kolling Institute, Faculty of Medicine and Health, University of Sydney and Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Kinghorn Centre for Clinical Genomics (R.L.D., K.R.K., C.P., A.E.M., V.G., A.C.M., M.E.D., M.J.C., C.M.S.), Garvan Institute of Medical Research, Darlinghurst; Department of Neurology (K.R.K., C.L., K.E.A., F.E.-H., C.M.S.), Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Dr. Kumar is now with Molecular Medicine Laboratory, Concord Hospital, Concord, New South Wales, Australia; Dr. Park is now with Cenyx Biotech, Jongno-gu, Seoul, South Korea; Brain and Mitochondrial Research Group (J.C.), Murdoch Children's Research Institute, Parkville, Melbourne; Department of Paediatrics (J.C.), University of Melbourne, Victoria; Prof. Schofield is now with GenIMPACT: Centre for Economic Impacts of Genomic Medicine, Macquarie University, Macquarie Park; Prof. Dinger is now with School of Biotechnology and Biomolecular Sciences, University of New South Wales, Randwick; and Prof. Cowley is now with Computational Biology Group, Children's Cancer Institute, University of New South Wales, Randwick, Australia.
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Clare Puttick
From the Department of Neurogenetics (R.L.D., K.R.K., C.L., K.E.A., F.E.-H., J.-S.P., C.M.S.), Kolling Institute, Faculty of Medicine and Health, University of Sydney and Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Kinghorn Centre for Clinical Genomics (R.L.D., K.R.K., C.P., A.E.M., V.G., A.C.M., M.E.D., M.J.C., C.M.S.), Garvan Institute of Medical Research, Darlinghurst; Department of Neurology (K.R.K., C.L., K.E.A., F.E.-H., C.M.S.), Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Dr. Kumar is now with Molecular Medicine Laboratory, Concord Hospital, Concord, New South Wales, Australia; Dr. Park is now with Cenyx Biotech, Jongno-gu, Seoul, South Korea; Brain and Mitochondrial Research Group (J.C.), Murdoch Children's Research Institute, Parkville, Melbourne; Department of Paediatrics (J.C.), University of Melbourne, Victoria; Prof. Schofield is now with GenIMPACT: Centre for Economic Impacts of Genomic Medicine, Macquarie University, Macquarie Park; Prof. Dinger is now with School of Biotechnology and Biomolecular Sciences, University of New South Wales, Randwick; and Prof. Cowley is now with Computational Biology Group, Children's Cancer Institute, University of New South Wales, Randwick, Australia.
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Christina Liang
From the Department of Neurogenetics (R.L.D., K.R.K., C.L., K.E.A., F.E.-H., J.-S.P., C.M.S.), Kolling Institute, Faculty of Medicine and Health, University of Sydney and Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Kinghorn Centre for Clinical Genomics (R.L.D., K.R.K., C.P., A.E.M., V.G., A.C.M., M.E.D., M.J.C., C.M.S.), Garvan Institute of Medical Research, Darlinghurst; Department of Neurology (K.R.K., C.L., K.E.A., F.E.-H., C.M.S.), Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Dr. Kumar is now with Molecular Medicine Laboratory, Concord Hospital, Concord, New South Wales, Australia; Dr. Park is now with Cenyx Biotech, Jongno-gu, Seoul, South Korea; Brain and Mitochondrial Research Group (J.C.), Murdoch Children's Research Institute, Parkville, Melbourne; Department of Paediatrics (J.C.), University of Melbourne, Victoria; Prof. Schofield is now with GenIMPACT: Centre for Economic Impacts of Genomic Medicine, Macquarie University, Macquarie Park; Prof. Dinger is now with School of Biotechnology and Biomolecular Sciences, University of New South Wales, Randwick; and Prof. Cowley is now with Computational Biology Group, Children's Cancer Institute, University of New South Wales, Randwick, Australia.
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Kate E. Ahmad
From the Department of Neurogenetics (R.L.D., K.R.K., C.L., K.E.A., F.E.-H., J.-S.P., C.M.S.), Kolling Institute, Faculty of Medicine and Health, University of Sydney and Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Kinghorn Centre for Clinical Genomics (R.L.D., K.R.K., C.P., A.E.M., V.G., A.C.M., M.E.D., M.J.C., C.M.S.), Garvan Institute of Medical Research, Darlinghurst; Department of Neurology (K.R.K., C.L., K.E.A., F.E.-H., C.M.S.), Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Dr. Kumar is now with Molecular Medicine Laboratory, Concord Hospital, Concord, New South Wales, Australia; Dr. Park is now with Cenyx Biotech, Jongno-gu, Seoul, South Korea; Brain and Mitochondrial Research Group (J.C.), Murdoch Children's Research Institute, Parkville, Melbourne; Department of Paediatrics (J.C.), University of Melbourne, Victoria; Prof. Schofield is now with GenIMPACT: Centre for Economic Impacts of Genomic Medicine, Macquarie University, Macquarie Park; Prof. Dinger is now with School of Biotechnology and Biomolecular Sciences, University of New South Wales, Randwick; and Prof. Cowley is now with Computational Biology Group, Children's Cancer Institute, University of New South Wales, Randwick, Australia.
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Fabienne Edema-Hildebrand
From the Department of Neurogenetics (R.L.D., K.R.K., C.L., K.E.A., F.E.-H., J.-S.P., C.M.S.), Kolling Institute, Faculty of Medicine and Health, University of Sydney and Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Kinghorn Centre for Clinical Genomics (R.L.D., K.R.K., C.P., A.E.M., V.G., A.C.M., M.E.D., M.J.C., C.M.S.), Garvan Institute of Medical Research, Darlinghurst; Department of Neurology (K.R.K., C.L., K.E.A., F.E.-H., C.M.S.), Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Dr. Kumar is now with Molecular Medicine Laboratory, Concord Hospital, Concord, New South Wales, Australia; Dr. Park is now with Cenyx Biotech, Jongno-gu, Seoul, South Korea; Brain and Mitochondrial Research Group (J.C.), Murdoch Children's Research Institute, Parkville, Melbourne; Department of Paediatrics (J.C.), University of Melbourne, Victoria; Prof. Schofield is now with GenIMPACT: Centre for Economic Impacts of Genomic Medicine, Macquarie University, Macquarie Park; Prof. Dinger is now with School of Biotechnology and Biomolecular Sciences, University of New South Wales, Randwick; and Prof. Cowley is now with Computational Biology Group, Children's Cancer Institute, University of New South Wales, Randwick, Australia.
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Jin-Sung Park
From the Department of Neurogenetics (R.L.D., K.R.K., C.L., K.E.A., F.E.-H., J.-S.P., C.M.S.), Kolling Institute, Faculty of Medicine and Health, University of Sydney and Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Kinghorn Centre for Clinical Genomics (R.L.D., K.R.K., C.P., A.E.M., V.G., A.C.M., M.E.D., M.J.C., C.M.S.), Garvan Institute of Medical Research, Darlinghurst; Department of Neurology (K.R.K., C.L., K.E.A., F.E.-H., C.M.S.), Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Dr. Kumar is now with Molecular Medicine Laboratory, Concord Hospital, Concord, New South Wales, Australia; Dr. Park is now with Cenyx Biotech, Jongno-gu, Seoul, South Korea; Brain and Mitochondrial Research Group (J.C.), Murdoch Children's Research Institute, Parkville, Melbourne; Department of Paediatrics (J.C.), University of Melbourne, Victoria; Prof. Schofield is now with GenIMPACT: Centre for Economic Impacts of Genomic Medicine, Macquarie University, Macquarie Park; Prof. Dinger is now with School of Biotechnology and Biomolecular Sciences, University of New South Wales, Randwick; and Prof. Cowley is now with Computational Biology Group, Children's Cancer Institute, University of New South Wales, Randwick, Australia.
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Andre E. Minoche
From the Department of Neurogenetics (R.L.D., K.R.K., C.L., K.E.A., F.E.-H., J.-S.P., C.M.S.), Kolling Institute, Faculty of Medicine and Health, University of Sydney and Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Kinghorn Centre for Clinical Genomics (R.L.D., K.R.K., C.P., A.E.M., V.G., A.C.M., M.E.D., M.J.C., C.M.S.), Garvan Institute of Medical Research, Darlinghurst; Department of Neurology (K.R.K., C.L., K.E.A., F.E.-H., C.M.S.), Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Dr. Kumar is now with Molecular Medicine Laboratory, Concord Hospital, Concord, New South Wales, Australia; Dr. Park is now with Cenyx Biotech, Jongno-gu, Seoul, South Korea; Brain and Mitochondrial Research Group (J.C.), Murdoch Children's Research Institute, Parkville, Melbourne; Department of Paediatrics (J.C.), University of Melbourne, Victoria; Prof. Schofield is now with GenIMPACT: Centre for Economic Impacts of Genomic Medicine, Macquarie University, Macquarie Park; Prof. Dinger is now with School of Biotechnology and Biomolecular Sciences, University of New South Wales, Randwick; and Prof. Cowley is now with Computational Biology Group, Children's Cancer Institute, University of New South Wales, Randwick, Australia.
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Velimir Gayevskiy
From the Department of Neurogenetics (R.L.D., K.R.K., C.L., K.E.A., F.E.-H., J.-S.P., C.M.S.), Kolling Institute, Faculty of Medicine and Health, University of Sydney and Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Kinghorn Centre for Clinical Genomics (R.L.D., K.R.K., C.P., A.E.M., V.G., A.C.M., M.E.D., M.J.C., C.M.S.), Garvan Institute of Medical Research, Darlinghurst; Department of Neurology (K.R.K., C.L., K.E.A., F.E.-H., C.M.S.), Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Dr. Kumar is now with Molecular Medicine Laboratory, Concord Hospital, Concord, New South Wales, Australia; Dr. Park is now with Cenyx Biotech, Jongno-gu, Seoul, South Korea; Brain and Mitochondrial Research Group (J.C.), Murdoch Children's Research Institute, Parkville, Melbourne; Department of Paediatrics (J.C.), University of Melbourne, Victoria; Prof. Schofield is now with GenIMPACT: Centre for Economic Impacts of Genomic Medicine, Macquarie University, Macquarie Park; Prof. Dinger is now with School of Biotechnology and Biomolecular Sciences, University of New South Wales, Randwick; and Prof. Cowley is now with Computational Biology Group, Children's Cancer Institute, University of New South Wales, Randwick, Australia.
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Amali C. Mallawaarachchi
From the Department of Neurogenetics (R.L.D., K.R.K., C.L., K.E.A., F.E.-H., J.-S.P., C.M.S.), Kolling Institute, Faculty of Medicine and Health, University of Sydney and Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Kinghorn Centre for Clinical Genomics (R.L.D., K.R.K., C.P., A.E.M., V.G., A.C.M., M.E.D., M.J.C., C.M.S.), Garvan Institute of Medical Research, Darlinghurst; Department of Neurology (K.R.K., C.L., K.E.A., F.E.-H., C.M.S.), Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Dr. Kumar is now with Molecular Medicine Laboratory, Concord Hospital, Concord, New South Wales, Australia; Dr. Park is now with Cenyx Biotech, Jongno-gu, Seoul, South Korea; Brain and Mitochondrial Research Group (J.C.), Murdoch Children's Research Institute, Parkville, Melbourne; Department of Paediatrics (J.C.), University of Melbourne, Victoria; Prof. Schofield is now with GenIMPACT: Centre for Economic Impacts of Genomic Medicine, Macquarie University, Macquarie Park; Prof. Dinger is now with School of Biotechnology and Biomolecular Sciences, University of New South Wales, Randwick; and Prof. Cowley is now with Computational Biology Group, Children's Cancer Institute, University of New South Wales, Randwick, Australia.
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John Christodoulou
From the Department of Neurogenetics (R.L.D., K.R.K., C.L., K.E.A., F.E.-H., J.-S.P., C.M.S.), Kolling Institute, Faculty of Medicine and Health, University of Sydney and Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Kinghorn Centre for Clinical Genomics (R.L.D., K.R.K., C.P., A.E.M., V.G., A.C.M., M.E.D., M.J.C., C.M.S.), Garvan Institute of Medical Research, Darlinghurst; Department of Neurology (K.R.K., C.L., K.E.A., F.E.-H., C.M.S.), Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Dr. Kumar is now with Molecular Medicine Laboratory, Concord Hospital, Concord, New South Wales, Australia; Dr. Park is now with Cenyx Biotech, Jongno-gu, Seoul, South Korea; Brain and Mitochondrial Research Group (J.C.), Murdoch Children's Research Institute, Parkville, Melbourne; Department of Paediatrics (J.C.), University of Melbourne, Victoria; Prof. Schofield is now with GenIMPACT: Centre for Economic Impacts of Genomic Medicine, Macquarie University, Macquarie Park; Prof. Dinger is now with School of Biotechnology and Biomolecular Sciences, University of New South Wales, Randwick; and Prof. Cowley is now with Computational Biology Group, Children's Cancer Institute, University of New South Wales, Randwick, Australia.
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Deborah Schofield
From the Department of Neurogenetics (R.L.D., K.R.K., C.L., K.E.A., F.E.-H., J.-S.P., C.M.S.), Kolling Institute, Faculty of Medicine and Health, University of Sydney and Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Kinghorn Centre for Clinical Genomics (R.L.D., K.R.K., C.P., A.E.M., V.G., A.C.M., M.E.D., M.J.C., C.M.S.), Garvan Institute of Medical Research, Darlinghurst; Department of Neurology (K.R.K., C.L., K.E.A., F.E.-H., C.M.S.), Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Dr. Kumar is now with Molecular Medicine Laboratory, Concord Hospital, Concord, New South Wales, Australia; Dr. Park is now with Cenyx Biotech, Jongno-gu, Seoul, South Korea; Brain and Mitochondrial Research Group (J.C.), Murdoch Children's Research Institute, Parkville, Melbourne; Department of Paediatrics (J.C.), University of Melbourne, Victoria; Prof. Schofield is now with GenIMPACT: Centre for Economic Impacts of Genomic Medicine, Macquarie University, Macquarie Park; Prof. Dinger is now with School of Biotechnology and Biomolecular Sciences, University of New South Wales, Randwick; and Prof. Cowley is now with Computational Biology Group, Children's Cancer Institute, University of New South Wales, Randwick, Australia.
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Marcel E. Dinger
From the Department of Neurogenetics (R.L.D., K.R.K., C.L., K.E.A., F.E.-H., J.-S.P., C.M.S.), Kolling Institute, Faculty of Medicine and Health, University of Sydney and Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Kinghorn Centre for Clinical Genomics (R.L.D., K.R.K., C.P., A.E.M., V.G., A.C.M., M.E.D., M.J.C., C.M.S.), Garvan Institute of Medical Research, Darlinghurst; Department of Neurology (K.R.K., C.L., K.E.A., F.E.-H., C.M.S.), Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Dr. Kumar is now with Molecular Medicine Laboratory, Concord Hospital, Concord, New South Wales, Australia; Dr. Park is now with Cenyx Biotech, Jongno-gu, Seoul, South Korea; Brain and Mitochondrial Research Group (J.C.), Murdoch Children's Research Institute, Parkville, Melbourne; Department of Paediatrics (J.C.), University of Melbourne, Victoria; Prof. Schofield is now with GenIMPACT: Centre for Economic Impacts of Genomic Medicine, Macquarie University, Macquarie Park; Prof. Dinger is now with School of Biotechnology and Biomolecular Sciences, University of New South Wales, Randwick; and Prof. Cowley is now with Computational Biology Group, Children's Cancer Institute, University of New South Wales, Randwick, Australia.
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Mark J. Cowley
From the Department of Neurogenetics (R.L.D., K.R.K., C.L., K.E.A., F.E.-H., J.-S.P., C.M.S.), Kolling Institute, Faculty of Medicine and Health, University of Sydney and Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Kinghorn Centre for Clinical Genomics (R.L.D., K.R.K., C.P., A.E.M., V.G., A.C.M., M.E.D., M.J.C., C.M.S.), Garvan Institute of Medical Research, Darlinghurst; Department of Neurology (K.R.K., C.L., K.E.A., F.E.-H., C.M.S.), Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Dr. Kumar is now with Molecular Medicine Laboratory, Concord Hospital, Concord, New South Wales, Australia; Dr. Park is now with Cenyx Biotech, Jongno-gu, Seoul, South Korea; Brain and Mitochondrial Research Group (J.C.), Murdoch Children's Research Institute, Parkville, Melbourne; Department of Paediatrics (J.C.), University of Melbourne, Victoria; Prof. Schofield is now with GenIMPACT: Centre for Economic Impacts of Genomic Medicine, Macquarie University, Macquarie Park; Prof. Dinger is now with School of Biotechnology and Biomolecular Sciences, University of New South Wales, Randwick; and Prof. Cowley is now with Computational Biology Group, Children's Cancer Institute, University of New South Wales, Randwick, Australia.
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Carolyn M. Sue
From the Department of Neurogenetics (R.L.D., K.R.K., C.L., K.E.A., F.E.-H., J.-S.P., C.M.S.), Kolling Institute, Faculty of Medicine and Health, University of Sydney and Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Kinghorn Centre for Clinical Genomics (R.L.D., K.R.K., C.P., A.E.M., V.G., A.C.M., M.E.D., M.J.C., C.M.S.), Garvan Institute of Medical Research, Darlinghurst; Department of Neurology (K.R.K., C.L., K.E.A., F.E.-H., C.M.S.), Royal North Shore Hospital, Northern Sydney Local Health District, St. Leonards; Dr. Kumar is now with Molecular Medicine Laboratory, Concord Hospital, Concord, New South Wales, Australia; Dr. Park is now with Cenyx Biotech, Jongno-gu, Seoul, South Korea; Brain and Mitochondrial Research Group (J.C.), Murdoch Children's Research Institute, Parkville, Melbourne; Department of Paediatrics (J.C.), University of Melbourne, Victoria; Prof. Schofield is now with GenIMPACT: Centre for Economic Impacts of Genomic Medicine, Macquarie University, Macquarie Park; Prof. Dinger is now with School of Biotechnology and Biomolecular Sciences, University of New South Wales, Randwick; and Prof. Cowley is now with Computational Biology Group, Children's Cancer Institute, University of New South Wales, Randwick, Australia.
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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
Neurology Aug 2022, 99 (7) e730-e742; DOI: 10.1212/WNL.0000000000200745

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Abstract

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.

Glossary

AMACR=
α-methylacyl-CoA racemase;
CNV=
copy number variation;
CPEO=
chronic progressive external ophthalmoplegia;
KSS=
Kearns-Sayre syndrome;
MD=
mitochondrial disease;
MELAS=
mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes;
MIDD=
maternally inherited deafness and diabetes;
MIM=
Mendelian inheritance in man;
mtDNA=
mitochondrial DNA;
nDNA=
nuclear DNA;
SNV=
single nucleotide variant;
SV=
structural variation;
VAF=
variant allele frequency;
VUS=
variants of uncertain significance;
WGS=
whole-genome sequencing

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • ↵* These authors contributed equally to this work as co-first authors.

  • ↵† These authors contributed equally to this work as co-senior authors.

  • The Article Processing Charge was funded by the authors.

  • Submitted and externally peer reviewed. The handling editors were Anthony Amato, MD, FAAN, and José Merino, MD, MPhil, FAAN.

  • Received September 18, 2021.
  • Accepted in final form April 4, 2022.
  • Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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  • Author Response: Use of Whole-Genome Sequencing for Mitochondrial Disease Diagnosis
    • Ryan L Davis, Research Fellow, University of Sydney
    • Kishore R Kumar, Neurologist, University of Sydney
    • Eloise Watson, Neurologist, University of Sydney
    • Carolyn M Sue, Neurologist, University of Sydney
    Submitted July 27, 2022
  • Reader Response: Use of Whole-Genome Sequencing for Mitochondrial Disease Diagnosis
    • Katherine R Schon, Clinical Research Fellow, University of Cambridge
    • Patrick F Chinnery, Neurologist, University of Cambridge
    Submitted July 14, 2022
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