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Neurology DOI:10.1212/WNL.0b013e3182918c40

Targeted exome sequencing of suspected mitochondrial disorders.

Publication TypeJournal Article
Year of Publication2013
AuthorsLieber, DS, Calvo, SE, Shanahan, K, Slate, NG, Liu, S, Hershman, SG, Gold, NB, Chapman, BA, Thorburn, DR, Berry, GT, Schmahmann, JD, Borowsky, ML, Mueller, DM, Sims, KB, Mootha, VK
Date Published2013 May 07
KeywordsAdolescent, Adult, Amino Acid Sequence, Child, Child, Preschool, DNA, Mitochondrial, Exome, Female, Gene Targeting, Genetic Predisposition to Disease, Humans, Infant, Infant, Newborn, Male, Middle Aged, Mitochondrial Diseases, Molecular Sequence Data, Pedigree, Sequence Analysis, DNA, Young Adult

OBJECTIVE: To evaluate the utility of targeted exome sequencing for the molecular diagnosis of mitochondrial disorders, which exhibit marked phenotypic and genetic heterogeneity.

METHODS: We considered a diverse set of 102 patients with suspected mitochondrial disorders based on clinical, biochemical, and/or molecular findings, and whose disease ranged from mild to severe, with varying age at onset. We sequenced the mitochondrial genome (mtDNA) and the exons of 1,598 nuclear-encoded genes implicated in mitochondrial biology, mitochondrial disease, or monogenic disorders with phenotypic overlap. We prioritized variants likely to underlie disease and established molecular diagnoses in accordance with current clinical genetic guidelines.

RESULTS: Targeted exome sequencing yielded molecular diagnoses in established disease loci in 22% of cases, including 17 of 18 (94%) with prior molecular diagnoses and 5 of 84 (6%) without. The 5 new diagnoses implicated 2 genes associated with canonical mitochondrial disorders (NDUFV1, POLG2), and 3 genes known to underlie other neurologic disorders (DPYD, KARS, WFS1), underscoring the phenotypic and biochemical overlap with other inborn errors. We prioritized variants in an additional 26 patients, including recessive, X-linked, and mtDNA variants that were enriched 2-fold over background and await further support of pathogenicity. In one case, we modeled patient mutations in yeast to provide evidence that recessive mutations in ATP5A1 can underlie combined respiratory chain deficiency.

CONCLUSION: The results demonstrate that targeted exome sequencing is an effective alternative to the sequential testing of mtDNA and individual nuclear genes as part of the investigation of mitochondrial disease. Our study underscores the ongoing challenge of variant interpretation in the clinical setting.


Alternate JournalNeurology
PubMed ID23596069
PubMed Central IDPMC3719425
Grant ListP30 DK040561 / DK / NIDDK NIH HHS / United States
RC2 HG005556 / HG / NHGRI NIH HHS / United States
R01 GM097136 / GM / NIGMS NIH HHS / United States
R01 GM066223 / GM / NIGMS NIH HHS / United States
R01GM66223 / GM / NIGMS NIH HHS / United States
RC2HG005556 / HG / NHGRI NIH HHS / United States