Trends in Genetics
ReviewMitochondrial Diseases: A Diagnostic Revolution
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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