Molecular Diagnosis of Infantile Mitochondrial Disease with Targeted Next-Generation Sequencing
Abstract
Applying next-generation sequencing to 42 infants with mitochondrial disease highlights both the potential and the challenge of using this technology in clinical diagnosis. Getting to the Genetic Root of Mitochondrial Disease Next-generation DNA sequencing is being applied with great success in research settings to uncover new disease genes. Despite these successes, it is unclear how useful the technology will be for routine clinical diagnosis given the challenge of interpreting DNA variations in individual patients. In a new study, Calvo and colleagues apply next-generation sequencing to infants with mitochondrial disorders, a large collection of inherited diseases that are notoriously difficult to diagnose because of the multitude of candidate genes and the highly variable nature of the clinical presentation. First, the authors selected 42 unrelated infants with mitochondrial diseases that were refractory to standard clinical genetic testing. Then, for each child, they sequenced the DNA of the mitochondrial genome, the 100 genes previously linked to mitochondrial disease, and the ~1000 additional genes that are known to participate in mitochondrial biology. Of all the DNA differences present in the patients, the researchers prioritized those that were rare in the general population, predicted to disrupt protein function, and inherited in a recessive fashion. Such variants showed fivefold enrichment in the patients compared to that in healthy control individuals. In 10…
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