Whole-genome sequencing technique helps identify, treat mitochondrial diseases
The mitochondria are organelles within the cells of all eukaryotic organisms that produce the energy to fuel the cells.
The mitochondria are organelles within the cells of all eukaryotic organisms that produce the energy to fuel the cells.
A class of rare but usually deadly diseases known as mitochondrial disorders occur when the mitochondria are unable to completely burn food and oxygen to generate energy. They are the most common type of heritable metabolic disorders and are a particularly difficult group of diseases to diagnose.
An interdisciplinary group of scientists at several Australian hospitals and research institutions is examining how the use of whole-genome sequencing might benefit the diagnosis of mitochondrial disease.
A peer-reviewed preprint of their work appears in the online journal Neurology April 4.
The study looked at 242 patients at a specialized mitochondrial disease clinic in Sydney, Australia. Of these, 62 had a “definite” diagnosis of mitochondrial disease, 108 were “probable” and 72 were “possible” cases.
Using whole-genome sequencing, the researchers were able to identify 130 of the subjects as having mitochondrial disease, which yields a diagnostic success rate of 53.7% (130/242) for this method.
Crucially, the ability of the whole-genome sequencing to identify the specific underlying molecular cause meant that precise treatment could be pursued, reproductive confidence could be established, and doctors knew better how to optimize patient management.
Unique quality of mitochondrial disease
As the authors point out, mitochondrial disorders are different because they can be caused by mutations in either the mitochondrial or nuclear genome and can affect both children and adults. Although some diagnosed with a mitochondrial disorder could have a nearly normal lifespan, a substantial number of children with the disorder do not reach adulthood, according to the Lily Foundation, the largest charitable funder of mitochondrial research in Europe.
Currently, no single genetic test is used in standard practice for treatment of mitochondrial disease. Reaching a definitive diagnosis, the authors point out, “may require sequencing of hundreds of nuclear genes and the majority of the mitochondrial genome, a process that has been impractical to date.”
Further complicating matters, the presence of disease-causing mitochondrial variants in blood declines with age, meaning that often-invasive sampling of other tissues may be required to achieve diagnosis.
Mitochondrial disease is more prevalent than is usually thought. Although one in 4,300 people develop diagnosable mitochondrial disease, prevalence studies have shown that 1 in 250 carry a gene variant that puts them at risk for developing a mitochondrial disorder. There are, thus, a large number of at-risk individuals who may be asymptomatic or only mildly symptomatic, but could pass the disorder on to their offspring.
Symptoms can arise in adults at different ages. They commonly include muscle weakness, fatigue, drooping eyelids (ptosis), weakness or paralysis of eye muscles (ophthalmoplegia), hearing loss, diabetes, seizures, nerve or sensory problems affecting specific areas (focal neurological deficits), and visual loss.
Whole-genome sequencing
Whole-genome sequencing refers to the process for determining the entirety or nearly the entirety of an organism’s DNA sequence occurring in both the nuclear and mitochondrial genes.
Since the first application of computing techniques to such studies more than 50 years ago, the cost and time required to complete a DNA sequence have been falling. Almost complete whole-genome sequencing can now be achieved in some cases for a cost under $1,000, according to a web post by Veritas Genetics. The effective cost for mitochondrial disease studies can be considerably more. However, rapid advances are expected to bring these costs down as well.
The authors conclude, “Comprehensive bigenomic [nuclear and mitochondrial DNA] sequencing accurately detects causative gene mutations in affected patients and simplifies mitochondrial disease diagnosis, enables early treatment, and informs the risk of genetic transmission.”
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Ryan L. Davis et al. Use of Whole-Genome Sequencing for Mitochondrial Disease Diagnosis. Neurology (April 2022).
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