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Researchers have identified the genetic root of severe mitochondrial disorders in infants whose cases couldn’t be solved by standard genetic testing, according to research published last week in Science Translational Medicine1.
The results are based on the sequencing of 1,000 genes that play a role in mitochondrial function.
The research is part of a growing trend of using cheaper, faster sequencing technology to read large swaths of the genome, rather than individual genes, to uncover the genetic basis of rare diseases.
“It reinforces the idea that one can learn a lot about disease by studying rare mutations, which I believe is very important for autism,” says J. Jay Gargus, professor of physiology and biophysics at the University of California, Irvine, who was not involved in the work. “The strongest leads we have for how to move forward in studying this disease come from rare syndromes.”
Disorders of the mitochondria, the cell’s energy source, affect roughly 1 in 5,000 people. They typically result from defects in genes within mitochondrial DNA or in mitochondria-linked genes that disrupt its function. The resulting symptoms vary greatly and can include learning disabilities, cognitive dysfunction and muscle weakness.
Mitochondrial disorders are also thought to play a role in a subset of autism cases. Some people with the disorder have signs of mitochondrial dysfunction, and some autism risk genes are linked to mitochondrial function.
In the new study, researchers sequenced the mitochondrial genome, as well as 100 genes previously linked to mitochondrial disorders and about 1,000 additional genes known to play a role in mitochondrial function, in 42 infants with mitochondrial disorders.
They filtered the resulting mutations, looking for those that are rare and would disrupt proteins.
The researchers compared the findings with data from nearly 400 healthy people whose genome sequences are part of a National Institutes of Health database. Although the sick infants and healthy controls have about the same number of rare, potentially disruptive mutations, the former are five times more likely to have mutations in both copies of the same gene.
In 10 of the infants, the researchers found mutations in genes previously linked to mitochondrial DNA and in 13 of them, they identified mutations in genes that had not previously been linked to the disorders. They were able to verify that the candidate mutation caused the disease in two of the infants.
“Our study is underscoring the promise and challenges of being able to do this in a clinically realistic scenario,” says lead investigator Vamsi Mootha, professor of systems biology and medicine at Harvard Medical School.
To diagnose mitochondrial disorders, physicians typically run biochemical tests on muscle or skin tissue taken from an individual. They can then search for the genetic culprit using commercial tests available for about 40 genes that have been linked to the disorders.
But running these tests one by one is time-consuming and expensive, and neglects hundreds of genes known to play a role in mitochondrial function.
As the cost of sequencing drops, researchers say it is becoming more cost-efficient to sequence hundreds or even thousands of genes simultaneously to search for mutations that drive an individual’s disease. Indeed, scientists and physicians across the globe are sequencing exomes — the protein-coding portion of the genome — of thousands of people with a variety of diseases.
Every sequenced genome reveals tens of thousands of new mutations, many of them harmless, making it challenging to pinpoint the disease-causing one.
In past studies, researchers have ruled out most of these irrelevant mutations by comparing the DNA from an individual with the disorder with that of healthy family members2.
Mootha’s team instead wanted to determine whether sequencing would work when DNA from family members isn’t available.
The researchers started with spontaneous cases of mitochondrial disorders, which are not inherited from another family member. Such cases are the ones most commonly seen in the clinic and also the most challenging to solve.
They were able to use their approach to diagnose 10 of 42 cases, and to identify candidate genes in another 13. In two of the latter cases, they were able to confirm the faulty gene by analyzing the molecular deficit in cells from the affected person. Introducing a normal version of the mutated gene into the cells corrected the problem.
One limitation of this approach is that it can’t detect so-called dominant mutations, those that can cause disease when only a single copy is inherited. To do so, researchers would need to examine healthy family members’ DNA to narrow down the list of candidate mutations.
Another is that they analyzed only the protein-coding regions of DNA, says Anu Suomalainen Wartiovaara, professor of clinical molecular medicine at the University of Helsinki, who was not involved with the work. This excludes regulatory regions, which direct when genes are produced, and which can also harbor disease-causing mutations. “But it’s quite remarkable that they can find so many genes,” she says.
Mootha says his work will have relevance beyond this limited set of disorders.
“We have reason to believe that mitochondrial genetic lesions might underlie other, more common, diseases, including neurodegenerative diseases such as Parkinson’s,” he says. Most cases of Parkinson’s disease are spontaneous, but some are hereditary, and a subset of those are linked to mitochondria, he says3.
Mootha’s team has built a resource of mitochondrial genes called MitoCarta, which Mootha plans to use to help collaborators who have already done whole-genome or exome sequencing of individuals with different disorders.
“We can help them interpret the one-twentieth of the exome dedicated to the mitochondria,” he says.
Mitochondrial disorders are also thought to play a role in some cases of autism. About five percent of children with autism appear to have an underlying problem with their mitochondria.
In collaboration with Mark Daly, associate professor of medicine at Harvard Medicine School, Mootha plans to analyze these genes in children with autism.
“They may likely constitute a more homogeneous molecular subgroup,” which in turn might make it easier to identify factors that can lead to autism, says Daly.
Gargus is also sequencing a subset of mitochondrial genes in children with autism and has identified some potential candidate mutations.
Given these links, should children who are diagnosed with autism have their mitochondrial genes analyzed? Not yet, says Gargus. “[But] I think the time will come when that will be most cost-effective thing to do.”
1: Calvo S.E. et al. Sci. Transl. Med. 4, 118ra10 (2012) PubMed
2: Roach J.C. et al. Science 328, 636-639 (2010) PubMed
3: Karbowski M. and A. Neutzner Acta Neuropathol. 123, 157-171 (2012) PubMed