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.
Disputes & Debates: Rapid online correspondence
- Author Response: Use of Whole-Genome Sequencing for Mitochondrial Disease Diagnosis
- Reader Response: Use of Whole-Genome Sequencing for Mitochondrial Disease Diagnosis
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