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Mitochondrial disorders are challenging to diagnose because they can be caused by mutations of mitochondrial DNA (mtDNA) or one of over 300 different nuclear genes.1 They tend to affect tissues with high energy requirements, either in isolation (such as the eye in Leber hereditary optic neuropathy) or many different organs including the nervous system. The features can overlap with common disorders such as migraine, diabetes mellitus or other rare disorders such as Charcot-Marie-Tooth disease and myasthenia gravis.2 The traditional approach to diagnosis relies on specific genetic or metabolic testing for characteristic clinical syndromes. If this is not definitive, patients undergo an invasive tissue biopsy (usually skeletal muscle) enabling histochemistry and biochemical testing.3 This approach is complex and can lead to a prolonged ‘diagnostic odyssey’.4 One survey showed that patients saw an average of eight clinicians before reaching a correct diagnosis, with 70% having a muscle biopsy.4 The approach to diagnosis of mitochondrial disorders is, however, undergoing a transformation, driven by the introduction of whole-exome sequencing5–8 and whole genome sequencing.9–11 (Whole exome sequencing and whole genome sequencing are both next generation sequencing methods. Whole exome sequencing looks at all the protein coding parts of the genes (exons) together with intron-exon boundaries, 3’ and 5’ untranslated regions and non-coding RNAs. This makes up only 1–2% of the whole genome. Whole genome sequencing looks at all the DNA including both the protein coding genes and non-coding regions.)
Whole-genome sequencing is well suited to investigating mitochondrial disorders because it captures …
Contributors KRS wrote the first draft which was critically edited and reviewed by PFC.
Funding PFC is a Wellcome Trust Principal Research Fellow (212219/Z/18/Z), and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UU_00028/7), the Medical Research Council (MRC) International Centre for Genomic Medicine in Neuromuscular Disease (MR/S005021/1) which also supports KRS, the Leverhulme Trust (RPG-2018-408), an MRC research grant (MR/S035699/1), an Alzheimer's Society Project Grant (AS-PG-18b-022). This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014).
Disclaimer The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed by Rhys Thomas, Newcastle-upon-Tyne, UK.