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Watson et al. J Transl Genet Genom 2020;4:188-202 I http://dx.doi.org/10.20517/jtgg.2020.31 Page 189

Keywords: Mitochondrial disease, diagnosis, next-generation sequencing, genetics

INTRODUCTION
Mitochondrial diseases comprise a diverse group of genetic disorders characterised by disrupted cellular
energy metabolism, which may arise due to mutations in either the mitochondrial (mtDNA) or nuclear
[1-4]
(nDNA) genome . Collectively, mitochondrial diseases represent the most common cause of inherited
[5]
[1]
metabolic disease , estimated to affect at least 1 in 8000 adults . However, population-based studies
indicate that the prevalence of mitochondrial disease may be as high as 1 in 250 adults, with the majority of
[6-8]
cases being under-recognised .
Present in all nucleated cells of the body, mitochondria are dynamic intracellular organelles that are
central to cellular homeostasis and metabolism. They host a variety of biochemical pathways and play a
[9]
primary role in energy generation . Consequently, mitochondrial diseases frequently manifest in tissues
[10]
with high energy requirements . Although mitochondrial diseases may present with one of many well-
defined clinical syndromes, clinical manifestations are protean, ranging from single organ, mild or oligo-
asymptomatic disease to severe or life-threatening multi-organ dysfunction. Moreover, symptoms and signs
may overlap with more common conditions and evolve throughout an individual’s lifespan [4,11-13] . Even
for experienced clinicians, the vast clinical and genetic variability can render specific genetic diagnoses
challenging, and the process may become a protracted “odyssey”, taking years before achieving molecular
diagnosis .
[14]
Mitochondrial medicine has seen substantial advances in diagnostic technologies over the last 50 years,
from the pre-molecular era of histological analysis of muscle to rapidly accelerating identification of the
molecular aetiologies of disease using next-generation sequencing (NGS) technologies. The notoriously
heterogeneous nature of mitochondrial diseases, their individual rarity, genotypic and phenotypic
variability and overlapping presentations with other genetic disorders, make them an ideal candidate group
for a non-targeted approach to genetic diagnosis. Although there remain important challenges to such an
approach, including optimising bioinformatic pipelines, classification and functional validation of variants
and cost, early studies support their utility [3,4,15-23] . Whole exome sequencing (WES) approaches have
markedly improved diagnostic yield, highlighted the genetic variability of diseases, facilitated the diagnosis
of monogenic mitochondrial mimics and advanced the understanding of mitochondrial biology, opening
up potential therapeutic avenues [3,4,15-23] . Whole genome sequencing (WGS) offers further potential, through
unbiased, simultaneous bigenomic sequencing with improved coverage, incorporation of non-coding
regions and excellent mtDNA coverage depth [24-26] .

The traditional and prevailing diagnostic approach, however, recapitulates the technological evolution in
mitochondrial disease diagnosis, moving from clinical evaluation to invasive biopsy and subsequently,
targeted sequencing, reserving WES or WGS for consideration in undiagnosed cases . In this article,
[4]
we briefly review the history of mitochondrial disease diagnosis, its evolution, impact and outstanding
challenges, and propose an alternative, minimally invasive “genetics first” approach, which complements
clinical evaluation with serum biomarkers for stratification, followed by exploratory bigenomic NGS.
Recourse to more invasive techniques, including muscle biopsy, is reserved for aetiological uncertainty,
identification of tissue-specific variants and functional validation of novel variants. Such an approach has
the potential to streamline diagnosis and limit invasive investigations, without increasing costs, whilst
optimising reciprocal gains in the understanding of mitochondrial biology and potential therapeutic
avenues.