DNA sequencing for difficult diagnoses of mitochondrial diseases may hit clinics soon

Identifying complete DNA sequences could identify difficult-to-diagnose diseases in humans. This concept is being used for the first time in a clinic. MitoExome sequencing uses new technologies known as next-generation sequencing (NGS) to decode all of the genes associated with mitochondria. Mitochondria are a capsule shaped organelle present within the cell. It is the powerhouse of the cell and its genes are inherited completely from the mother.

The technique that involves decoding thousands of genes simultaneously has been used in laboratories to uncover genes related to diseases since 2009. Now it has successfully moved to the clinic, where patients do not know what is wrong with them and may not know their family history of disease, and clinicians have few clues about which genes might be causing the problem. The technique targets mitochondrial diseases, which affect the way the body produces energy and are difficult to diagnose.

Found in at least one in every 5000 people, the diseases often involve many genes, and symptoms vary across organs. For example, common manifestations can include blindness, seizures, slow digestion and muscle pain. Currently, diagnosing such disorders can take months or even years, and involves an invasive muscle biopsy. DNA sequencing technology may help to speed things up.

For the latest study S Calvo, Elena Tucker and colleagues from the Murdoch Childrens Research Institute in Sydney, Australia, along with Vamsi Mootha from Harvard Medical School sequenced the genomes of 42 children who had traits that suggested they carry a mitochondrial disorder. The team looked at both DNA and mitochondria and at the 100 or so genes within their nuclear DNA that have already been linked to mitochondrial diseases. They also looked at a further 1000 nuclear genes that play a part in mitochondrial biology. Finally the genomes were compared to databases of genetic variation recorded in the general population.

Ten of the children had mutations in genes previously linked to mitochondrial diseases, and so could be given a precise diagnosis. Mutations not previously associated with any disease were found in another 13 children. Tucker says that these patients can expect a full diagnosis once studies confirm the function of these genes. “We are quite excited,” says Tucker. “Most of these diagnoses were in children whose [illnesses] could not easily be diagnosed using traditional methods.”

“What we’re hoping from this new technology is to be able to replace the current diagnostic journey that involves many specialists and a lot of diagnostic time with a single test, either of the blood or affected tissue,” said Calvo, a senior computational biologist at the Broad Institute and first author of the paper. “We asked, based on the genetic analysis of this sample, do we have a very high confidence that this is the diagnosis for this patient?” “Our long-term vision is to develop novel therapeutics with companion diagnostics,” said Mootha, a senior author of the paper and senior associate member at the Broad Institute and physician-scientist at Massachusetts General Hospital. “These are uniformly fatal diseases. There isn’t a single proven therapy. This is what motivates us.”

A few years ago, or maybe even one year ago, the cost of sequencing one individual’s DNA was too prohibitive to even think of using clinically. Now that the cost of sequencing one genome has come down to around $1000 and will probably come down even lower, genome sequencing will soon be cheaper than ordering more than two or three individual genetic tests.

Michael Ryan, a biochemist at La Trobe University in Melbourne, Australia, who was not involved in the work, says the diagnosis rate “will improve” within the next couple of years as the list of genes known to be linked to mitochondrial diseases grows, and it becomes clearer how mutations combine to cause diseases. “It's a fantastic study,” added Matthew McKenzie at Monash University in Melbourne. Finding genetic mutations in mitochondrial patients is “like searching for a needle in a haystack”, he said. “I think it was a very good result to transfer to a clinical setting.”

“For a quarter of the patients where molecular diagnosis wasn’t possible before, we can pretty easily find the diagnosis now,” said Calvo. Based on further analysis, the team estimates that next-generation sequencing could be used to establish a diagnosis for about half of the general population of infants with mitochondrial disorders. As the database of genome variation expands, so will their ability to diagnose infants with these diseases. “But this is a caution as well,” said Calvo. “This technology is not going to immediately solve all of the cases.”

Researchers estimate that mutations in more than 200 different mitochondrial genes could give rise to mitochondrial diseases, but to date, only about 100 of these disease genes have been identified. “Companies are beginning to offer sequencing services, and many patients are asking their physicians about them, but clinicians are wary,” Calvo said. “But now that studies like this are being published, clinicians can come back to their patients and explain what they can expect.”

Their results appear online January 25 in journal Science Translational Medicine.

Dr. Ananya Mandal

Written by

Dr. Ananya Mandal

Dr. Ananya Mandal is a doctor by profession, lecturer by vocation and a medical writer by passion. She specialized in Clinical Pharmacology after her bachelor's (MBBS). For her, health communication is not just writing complicated reviews for professionals but making medical knowledge understandable and available to the general public as well.


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