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Mitochondrial DNA variants in genomic data: diagnostic uplifts and predictive implications

Nature Reviews Genetics volume 22, pages 547–548 (2021)Cite this article

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A broad spectrum of rare disease presentations can now be investigated by analysing mitochondrial DNA (mtDNA) variants from whole-genome sequencing (WGS) data. However, mtDNA mutations may cause unanticipated, extended phenotypes and have reproductive implications. We recommend that these be considered by patients and clinicians before embarking on WGS.

Primary mitochondrial diseases (PMDs) comprise a diverse group of conditions defined by impaired oxidative phosphorylation or other aspects of mitochondrial function. They are unique among genetic disorders in that they are caused by mutations in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA), a small circular molecule, multiple copies of which reside within each mitochondrion, with hundreds to thousands of mitochondria in each cell. Mutations can exist in all mtDNA molecules (homoplasmy) or a proportion (heteroplasmy); the level of mtDNA heteroplasmy may vary between tissues and change over time. Among others, PMDs may present as metabolic or developmental syndromes, neurogenetic and neuromuscular disorders, cardiomyopathy, monogenic diabetes, deafness, or inherited eye diseases.

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References

  1. Macken, W. L., Vandrovcova, J., Hanna, M. G. & Pitceathly, R. D. S. Applying genomic and transcriptomic advances to mitochondrial medicine. Nat. Rev. Neurol. 17, 215–230 (2021).

    Article  Google Scholar 

  2. Poole, O. V. et al. Mitochondrial DNA analysis from exome sequencing data improves the diagnostic yield in neurological diseases. Ann. Neurol. 89, 1240–1247 (2021).

    Article  CAS  Google Scholar 

  3. Raymond, F. L., Horvath, R. & Chinnery, P. F. First-line genomic diagnosis of mitochondrial disorders. Nat. Rev. Genet. 19, 399–400 (2018).

    Article  CAS  Google Scholar 

  4. Naing, A. et al. Maternally inherited diabetes and deafness (MIDD): diagnosis and management. J. Diabetes Complications 28, 542–546 (2014).

    Article  Google Scholar 

  5. Chiaratti, M. R. et al. Maternal transmission of mitochondrial diseases. Genet. Mol. Biol. 43 (1 Suppl. 1), e20190095 (2020).

    Article  CAS  Google Scholar 

  6. Gorman, G. S., McFarland, R., Stewart, J., Feeney, C. & Turnbull, D. M. Mitochondrial donation: from test tube to clinic. Lancet 392, 1191–1192 (2018).

    Article  Google Scholar 

  7. Miller, D. T. et al. ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet. Med. https://doi.org/10.1038/s41436-021-01172-3 (2021).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

R.D.S.P. is supported by a Medical Research Council (UK) Clinician Scientist Fellowship (MR/S002065/1). W.L.M., M.G.H. and R.D.S.P. receive funding from a Medical Research Council (UK) strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) (MR/S005021/1). A.M.L. is supported by funding from a Wellcome Trust collaborative award 208053/Z/17/Z.

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Authors and Affiliations

  1. Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK

    William L. Macken, Michael G. Hanna & Robert D. S. Pitceathly

  2. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK

    William L. Macken & Anneke M. Lucassen

  3. Clinical Ethics and Law Group (CELS), Faculty of Medicine, University of Southampton, Southampton, UK

    Anneke M. Lucassen

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  1. William L. Macken
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  2. Anneke M. Lucassen
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  3. Michael G. Hanna
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  4. Robert D. S. Pitceathly
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Correspondence to Robert D. S. Pitceathly.

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Competing interests

A.M.L. is a member of the Ethics Advisory Committee for Genomics England. The other authors declare no competing interests.

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Macken, W.L., Lucassen, A.M., Hanna, M.G. et al. Mitochondrial DNA variants in genomic data: diagnostic uplifts and predictive implications. Nat Rev Genet 22, 547–548 (2021). https://doi.org/10.1038/s41576-021-00381-5

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  • DOI: https://doi.org/10.1038/s41576-021-00381-5

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