Trends in Genetics

Trends in Genetics

Volume 36, Issue 9, September 2020, Pages 702-717
Journal home page for Trends in Genetics

Review
Mitochondrial Diseases: A Diagnostic Revolution

https://doi.org/10.1016/j.tig.2020.06.009Get rights and content

Highlights

  • Reaching a molecular diagnosis in a patient with mitochondrial disease can be a complex process, both clinically and genetically.

  • The diagnostic process for mitochondrial disease is undergoing a dramatic transition, moving away from a histological and biochemical approach to a primarily genetic approach.

  • Whole-genome sequencing (WGS) can provide a genetic diagnosis for most patients. This has the added advantage of being able to diagnose mitochondrial disease in patients not thought to have the disorder, and to diagnose other non-mitochondrial diseases that resemble mitochondrial disorders.

  • When WGS is negative, complementary phenotyping and sequencing approaches provide an additional strategy to increase the diagnostic yield.

  • A collaborative community of clinicians and researchers allows extensive data-sharing across the globe, accelerating gene discovery and improving our understanding of how mutations cause disease.

Mitochondrial disorders have emerged as a common cause of inherited disease, but are traditionally viewed as being difficult to diagnose clinically, and even more difficult to comprehensively characterize at the molecular level. However, new sequencing approaches, particularly whole-genome sequencing (WGS), have dramatically changed the landscape. The combined analysis of nuclear and mitochondrial DNA (mtDNA) allows rapid diagnosis for the vast majority of patients, but new challenges have emerged. We review recent discoveries that will benefit patients and families, and highlight emerging questions that remain to be resolved.

Section snippets

Background – The Challenge of Mitochondrial Disorders

Mitochondrial disorders (see Glossary) are caused by mutations in genes that primarily affect oxidative phosphorylation and ATP synthesis [1]. As a group, they affect ~1:5000 of the population [2,3], although the prevalence is likely to increase as new mitochondrial disease genes are identified. We review here the challenges that a clinician faces when trying to reach a genetic diagnosis for a patient or family with a suspected mitochondrial disease. We discuss the impact of new sequencing

The Diagnostic Challenge

Although mtDNA and nuclear gene defects ultimately compromise oxidative phosphorylation and/or ATP synthesis, the disease mechanisms are more complex, muddying the relationship between genotype and phenotype. Mutations in different genes can cause the same phenotype: for example, there are at least 75 known causes of Leigh syndrome, involving both the nuclear genome and mtDNA [19,20]. In addition, the same pathogenic mutation can cause a range of different phenotypes. For example, the m.3243A>G

Next-Generation Sequencing for Mitochondrial Disease Genes

In this section we explain how the development and subsequent application of massively parallel DNA sequencing over the past decade has transformed our understanding of mitochondrial disorders.

Genotype-Driven Approaches

Our ability to identify new mitochondrial disease genes has been greatly helped through international efforts for data sharing. Initially beginning on an ad hoc basis between leading centers, there are now mitochondria-specific [67,68] and more general platforms [69] to facilitate segregation analysis of novel variants in new disease genes. This remains the most powerful way of proving causality (Box 3).

Transcriptomic Approaches

Sequencing of RNA (the transcriptome), either alone or in parallel to sequencing of DNA (the

Emerging Common Mechanisms

Many of the first genes to be associated with mitochondrial disorders encoded structural subunits of the respiratory chain that are encoded by both mtDNA and nuclear genes. However, our expanding knowledge of the genomic basis of mitochondrial disorders is revealing several other common mechanisms.

Phenotype Modulators: Genetic and Environmental Factors

Variable clinical penetrance presents an additional challenge when diagnosing mitochondrial disorders. Perhaps the best example is also the most common mitochondrial disorder – LHON – which in Europeans is usually caused by one of three common mutations in the coding region of MT-ND genes: m.11778G>A, m.3460G>A, and m.14484T>C [95]. Recent population studies have shown that these mtDNA mutations are carried by approximately 1:300 of the population on multiple different mtDNA genetic

Concluding Remarks

Falling costs mean that WGS has become an affordable clinical test in Western societies, leading to a diagnostic revolution for mitochondrial disorders. The evidence reviewed here supports a WGS-first approach for the investigation of mitochondrial disease. This should be offered to all patients who do not fall neatly into the small group of instantly recognizable syndromes caused by a handful of specific mutations or mtDNA deletions. To investigate unsolvable cases, transcriptomic,

Acknowledgments

P.F.C. is a Wellcome Trust Principal Research Fellow (212219/Z/18/Z) and a UK National Institute of Health research (NIHR) Senior Investigator, and receives support from the MRC Mitochondrial Biology Unit (MC_UU_00015/9), the MRC International Centre for Genomic Medicine in Neuromuscular Disease (MR/S005021/1), the Leverhulme Trust (RPG-2018-408), an MRC research grant (MR/S035699/1), an Alzheimer's Society project grant (AS-PG-18b-022), and the NIHR Biomedical Research Centre based at

Glossary

Chronic progressive external ophthalmoplegia (CPEO)
an eye condition in which weakness of the extraocular muscles causes ptosis (droopy eyelids) and limitation of eye movements.
Heteroplasmy
the presence of more than one mtDNA type in the same cell, tissue, or individual. A heteroplasmic mtDNA variant is present in a proportion of mtDNA molecules.
Homoplasmy
a condition in which all copies of the mtDNA are the same: either all normal mtDNA or all mutant mtDNA.
Leber hereditary optic neuropathy (LHON)

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