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May 07, 2013; 80 (19) Article

Targeted exome sequencing of suspected mitochondrial disorders

Daniel S. Lieber, Sarah E. Calvo, Kristy Shanahan, Nancy G. Slate, Shangtao Liu, Steven G. Hershman, Nina B. Gold, Brad A. Chapman, David R. Thorburn, Gerard T. Berry, Jeremy D. Schmahmann, Mark L. Borowsky, David M. Mueller, Katherine B. Sims, Vamsi K. Mootha
First published April 17, 2013, DOI: https://doi.org/10.1212/WNL.0b013e3182918c40
Daniel S. Lieber
From the Department of Molecular Biology (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., B.A.C., M.L.B., V.K.M.) and Center for Human Genetic Research (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., K.B.S., V.K.M.), Massachusetts General Hospital, Boston; Department of Systems Biology (D.S.L., S.E.C., S.G.H., V.K.M.), Harvard Medical School, Boston; Broad Institute of Harvard and MIT (D.S.L., S.E.C., S.G.H., V.K.M.), Cambridge, MA; Department of Biochemistry and Molecular Biology (K.S., D.M.M.), Chicago Medical School, Rosalind Franklin University of Medicine and Science, Chicago, IL; Murdoch Childrens Research Institute (D.R.T.), Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Australia; Harvard Medical School (G.T.B.), The Manton Center for Orphan Disease Research, Children's Hospital Boston; Department of Neurology (J.D.S., K.B.S.), Massachusetts General Hospital & Harvard Medical School, Boston; and Department of Medicine (V.K.M.), Massachusetts General Hospital, Boston, MA.
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Sarah E. Calvo
From the Department of Molecular Biology (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., B.A.C., M.L.B., V.K.M.) and Center for Human Genetic Research (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., K.B.S., V.K.M.), Massachusetts General Hospital, Boston; Department of Systems Biology (D.S.L., S.E.C., S.G.H., V.K.M.), Harvard Medical School, Boston; Broad Institute of Harvard and MIT (D.S.L., S.E.C., S.G.H., V.K.M.), Cambridge, MA; Department of Biochemistry and Molecular Biology (K.S., D.M.M.), Chicago Medical School, Rosalind Franklin University of Medicine and Science, Chicago, IL; Murdoch Childrens Research Institute (D.R.T.), Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Australia; Harvard Medical School (G.T.B.), The Manton Center for Orphan Disease Research, Children's Hospital Boston; Department of Neurology (J.D.S., K.B.S.), Massachusetts General Hospital & Harvard Medical School, Boston; and Department of Medicine (V.K.M.), Massachusetts General Hospital, Boston, MA.
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Kristy Shanahan
From the Department of Molecular Biology (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., B.A.C., M.L.B., V.K.M.) and Center for Human Genetic Research (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., K.B.S., V.K.M.), Massachusetts General Hospital, Boston; Department of Systems Biology (D.S.L., S.E.C., S.G.H., V.K.M.), Harvard Medical School, Boston; Broad Institute of Harvard and MIT (D.S.L., S.E.C., S.G.H., V.K.M.), Cambridge, MA; Department of Biochemistry and Molecular Biology (K.S., D.M.M.), Chicago Medical School, Rosalind Franklin University of Medicine and Science, Chicago, IL; Murdoch Childrens Research Institute (D.R.T.), Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Australia; Harvard Medical School (G.T.B.), The Manton Center for Orphan Disease Research, Children's Hospital Boston; Department of Neurology (J.D.S., K.B.S.), Massachusetts General Hospital & Harvard Medical School, Boston; and Department of Medicine (V.K.M.), Massachusetts General Hospital, Boston, MA.
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Nancy G. Slate
From the Department of Molecular Biology (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., B.A.C., M.L.B., V.K.M.) and Center for Human Genetic Research (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., K.B.S., V.K.M.), Massachusetts General Hospital, Boston; Department of Systems Biology (D.S.L., S.E.C., S.G.H., V.K.M.), Harvard Medical School, Boston; Broad Institute of Harvard and MIT (D.S.L., S.E.C., S.G.H., V.K.M.), Cambridge, MA; Department of Biochemistry and Molecular Biology (K.S., D.M.M.), Chicago Medical School, Rosalind Franklin University of Medicine and Science, Chicago, IL; Murdoch Childrens Research Institute (D.R.T.), Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Australia; Harvard Medical School (G.T.B.), The Manton Center for Orphan Disease Research, Children's Hospital Boston; Department of Neurology (J.D.S., K.B.S.), Massachusetts General Hospital & Harvard Medical School, Boston; and Department of Medicine (V.K.M.), Massachusetts General Hospital, Boston, MA.
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Shangtao Liu
From the Department of Molecular Biology (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., B.A.C., M.L.B., V.K.M.) and Center for Human Genetic Research (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., K.B.S., V.K.M.), Massachusetts General Hospital, Boston; Department of Systems Biology (D.S.L., S.E.C., S.G.H., V.K.M.), Harvard Medical School, Boston; Broad Institute of Harvard and MIT (D.S.L., S.E.C., S.G.H., V.K.M.), Cambridge, MA; Department of Biochemistry and Molecular Biology (K.S., D.M.M.), Chicago Medical School, Rosalind Franklin University of Medicine and Science, Chicago, IL; Murdoch Childrens Research Institute (D.R.T.), Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Australia; Harvard Medical School (G.T.B.), The Manton Center for Orphan Disease Research, Children's Hospital Boston; Department of Neurology (J.D.S., K.B.S.), Massachusetts General Hospital & Harvard Medical School, Boston; and Department of Medicine (V.K.M.), Massachusetts General Hospital, Boston, MA.
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Steven G. Hershman
From the Department of Molecular Biology (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., B.A.C., M.L.B., V.K.M.) and Center for Human Genetic Research (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., K.B.S., V.K.M.), Massachusetts General Hospital, Boston; Department of Systems Biology (D.S.L., S.E.C., S.G.H., V.K.M.), Harvard Medical School, Boston; Broad Institute of Harvard and MIT (D.S.L., S.E.C., S.G.H., V.K.M.), Cambridge, MA; Department of Biochemistry and Molecular Biology (K.S., D.M.M.), Chicago Medical School, Rosalind Franklin University of Medicine and Science, Chicago, IL; Murdoch Childrens Research Institute (D.R.T.), Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Australia; Harvard Medical School (G.T.B.), The Manton Center for Orphan Disease Research, Children's Hospital Boston; Department of Neurology (J.D.S., K.B.S.), Massachusetts General Hospital & Harvard Medical School, Boston; and Department of Medicine (V.K.M.), Massachusetts General Hospital, Boston, MA.
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Nina B. Gold
From the Department of Molecular Biology (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., B.A.C., M.L.B., V.K.M.) and Center for Human Genetic Research (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., K.B.S., V.K.M.), Massachusetts General Hospital, Boston; Department of Systems Biology (D.S.L., S.E.C., S.G.H., V.K.M.), Harvard Medical School, Boston; Broad Institute of Harvard and MIT (D.S.L., S.E.C., S.G.H., V.K.M.), Cambridge, MA; Department of Biochemistry and Molecular Biology (K.S., D.M.M.), Chicago Medical School, Rosalind Franklin University of Medicine and Science, Chicago, IL; Murdoch Childrens Research Institute (D.R.T.), Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Australia; Harvard Medical School (G.T.B.), The Manton Center for Orphan Disease Research, Children's Hospital Boston; Department of Neurology (J.D.S., K.B.S.), Massachusetts General Hospital & Harvard Medical School, Boston; and Department of Medicine (V.K.M.), Massachusetts General Hospital, Boston, MA.
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Brad A. Chapman
From the Department of Molecular Biology (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., B.A.C., M.L.B., V.K.M.) and Center for Human Genetic Research (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., K.B.S., V.K.M.), Massachusetts General Hospital, Boston; Department of Systems Biology (D.S.L., S.E.C., S.G.H., V.K.M.), Harvard Medical School, Boston; Broad Institute of Harvard and MIT (D.S.L., S.E.C., S.G.H., V.K.M.), Cambridge, MA; Department of Biochemistry and Molecular Biology (K.S., D.M.M.), Chicago Medical School, Rosalind Franklin University of Medicine and Science, Chicago, IL; Murdoch Childrens Research Institute (D.R.T.), Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Australia; Harvard Medical School (G.T.B.), The Manton Center for Orphan Disease Research, Children's Hospital Boston; Department of Neurology (J.D.S., K.B.S.), Massachusetts General Hospital & Harvard Medical School, Boston; and Department of Medicine (V.K.M.), Massachusetts General Hospital, Boston, MA.
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David R. Thorburn
From the Department of Molecular Biology (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., B.A.C., M.L.B., V.K.M.) and Center for Human Genetic Research (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., K.B.S., V.K.M.), Massachusetts General Hospital, Boston; Department of Systems Biology (D.S.L., S.E.C., S.G.H., V.K.M.), Harvard Medical School, Boston; Broad Institute of Harvard and MIT (D.S.L., S.E.C., S.G.H., V.K.M.), Cambridge, MA; Department of Biochemistry and Molecular Biology (K.S., D.M.M.), Chicago Medical School, Rosalind Franklin University of Medicine and Science, Chicago, IL; Murdoch Childrens Research Institute (D.R.T.), Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Australia; Harvard Medical School (G.T.B.), The Manton Center for Orphan Disease Research, Children's Hospital Boston; Department of Neurology (J.D.S., K.B.S.), Massachusetts General Hospital & Harvard Medical School, Boston; and Department of Medicine (V.K.M.), Massachusetts General Hospital, Boston, MA.
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Gerard T. Berry
From the Department of Molecular Biology (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., B.A.C., M.L.B., V.K.M.) and Center for Human Genetic Research (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., K.B.S., V.K.M.), Massachusetts General Hospital, Boston; Department of Systems Biology (D.S.L., S.E.C., S.G.H., V.K.M.), Harvard Medical School, Boston; Broad Institute of Harvard and MIT (D.S.L., S.E.C., S.G.H., V.K.M.), Cambridge, MA; Department of Biochemistry and Molecular Biology (K.S., D.M.M.), Chicago Medical School, Rosalind Franklin University of Medicine and Science, Chicago, IL; Murdoch Childrens Research Institute (D.R.T.), Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Australia; Harvard Medical School (G.T.B.), The Manton Center for Orphan Disease Research, Children's Hospital Boston; Department of Neurology (J.D.S., K.B.S.), Massachusetts General Hospital & Harvard Medical School, Boston; and Department of Medicine (V.K.M.), Massachusetts General Hospital, Boston, MA.
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Jeremy D. Schmahmann
From the Department of Molecular Biology (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., B.A.C., M.L.B., V.K.M.) and Center for Human Genetic Research (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., K.B.S., V.K.M.), Massachusetts General Hospital, Boston; Department of Systems Biology (D.S.L., S.E.C., S.G.H., V.K.M.), Harvard Medical School, Boston; Broad Institute of Harvard and MIT (D.S.L., S.E.C., S.G.H., V.K.M.), Cambridge, MA; Department of Biochemistry and Molecular Biology (K.S., D.M.M.), Chicago Medical School, Rosalind Franklin University of Medicine and Science, Chicago, IL; Murdoch Childrens Research Institute (D.R.T.), Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Australia; Harvard Medical School (G.T.B.), The Manton Center for Orphan Disease Research, Children's Hospital Boston; Department of Neurology (J.D.S., K.B.S.), Massachusetts General Hospital & Harvard Medical School, Boston; and Department of Medicine (V.K.M.), Massachusetts General Hospital, Boston, MA.
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Mark L. Borowsky
From the Department of Molecular Biology (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., B.A.C., M.L.B., V.K.M.) and Center for Human Genetic Research (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., K.B.S., V.K.M.), Massachusetts General Hospital, Boston; Department of Systems Biology (D.S.L., S.E.C., S.G.H., V.K.M.), Harvard Medical School, Boston; Broad Institute of Harvard and MIT (D.S.L., S.E.C., S.G.H., V.K.M.), Cambridge, MA; Department of Biochemistry and Molecular Biology (K.S., D.M.M.), Chicago Medical School, Rosalind Franklin University of Medicine and Science, Chicago, IL; Murdoch Childrens Research Institute (D.R.T.), Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Australia; Harvard Medical School (G.T.B.), The Manton Center for Orphan Disease Research, Children's Hospital Boston; Department of Neurology (J.D.S., K.B.S.), Massachusetts General Hospital & Harvard Medical School, Boston; and Department of Medicine (V.K.M.), Massachusetts General Hospital, Boston, MA.
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David M. Mueller
From the Department of Molecular Biology (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., B.A.C., M.L.B., V.K.M.) and Center for Human Genetic Research (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., K.B.S., V.K.M.), Massachusetts General Hospital, Boston; Department of Systems Biology (D.S.L., S.E.C., S.G.H., V.K.M.), Harvard Medical School, Boston; Broad Institute of Harvard and MIT (D.S.L., S.E.C., S.G.H., V.K.M.), Cambridge, MA; Department of Biochemistry and Molecular Biology (K.S., D.M.M.), Chicago Medical School, Rosalind Franklin University of Medicine and Science, Chicago, IL; Murdoch Childrens Research Institute (D.R.T.), Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Australia; Harvard Medical School (G.T.B.), The Manton Center for Orphan Disease Research, Children's Hospital Boston; Department of Neurology (J.D.S., K.B.S.), Massachusetts General Hospital & Harvard Medical School, Boston; and Department of Medicine (V.K.M.), Massachusetts General Hospital, Boston, MA.
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Katherine B. Sims
From the Department of Molecular Biology (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., B.A.C., M.L.B., V.K.M.) and Center for Human Genetic Research (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., K.B.S., V.K.M.), Massachusetts General Hospital, Boston; Department of Systems Biology (D.S.L., S.E.C., S.G.H., V.K.M.), Harvard Medical School, Boston; Broad Institute of Harvard and MIT (D.S.L., S.E.C., S.G.H., V.K.M.), Cambridge, MA; Department of Biochemistry and Molecular Biology (K.S., D.M.M.), Chicago Medical School, Rosalind Franklin University of Medicine and Science, Chicago, IL; Murdoch Childrens Research Institute (D.R.T.), Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Australia; Harvard Medical School (G.T.B.), The Manton Center for Orphan Disease Research, Children's Hospital Boston; Department of Neurology (J.D.S., K.B.S.), Massachusetts General Hospital & Harvard Medical School, Boston; and Department of Medicine (V.K.M.), Massachusetts General Hospital, Boston, MA.
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Vamsi K. Mootha
From the Department of Molecular Biology (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., B.A.C., M.L.B., V.K.M.) and Center for Human Genetic Research (D.S.L., S.E.C., N.G.S., S.L., S.G.H., N.B.G., K.B.S., V.K.M.), Massachusetts General Hospital, Boston; Department of Systems Biology (D.S.L., S.E.C., S.G.H., V.K.M.), Harvard Medical School, Boston; Broad Institute of Harvard and MIT (D.S.L., S.E.C., S.G.H., V.K.M.), Cambridge, MA; Department of Biochemistry and Molecular Biology (K.S., D.M.M.), Chicago Medical School, Rosalind Franklin University of Medicine and Science, Chicago, IL; Murdoch Childrens Research Institute (D.R.T.), Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Australia; Harvard Medical School (G.T.B.), The Manton Center for Orphan Disease Research, Children's Hospital Boston; Department of Neurology (J.D.S., K.B.S.), Massachusetts General Hospital & Harvard Medical School, Boston; and Department of Medicine (V.K.M.), Massachusetts General Hospital, Boston, MA.
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Citation
Targeted exome sequencing of suspected mitochondrial disorders
Daniel S. Lieber, Sarah E. Calvo, Kristy Shanahan, Nancy G. Slate, Shangtao Liu, Steven G. Hershman, Nina B. Gold, Brad A. Chapman, David R. Thorburn, Gerard T. Berry, Jeremy D. Schmahmann, Mark L. Borowsky, David M. Mueller, Katherine B. Sims, Vamsi K. Mootha
Neurology May 2013, 80 (19) 1762-1770; DOI: 10.1212/WNL.0b013e3182918c40

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Abstract

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.

GLOSSARY

AF=
allele frequency;
ATP=
adenosine triphosphate;
DPD=
dihydropyrimidine dehydrogenase;
ETC=
electron transport chain;
MGH=
Massachusetts General Hospital;
mgi=
mitochondrial genome integrity;
mtDNA=
mitochondrial DNA;
NGS=
next-generation sequencing;
OMIM=
Online Mendelian Inheritance in Man;
OXPHOS=
oxidative phosphorylation;
pVUS=
prioritized variant of unknown significance

Footnotes

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Supplemental data at www.neurology.org

  • Received July 30, 2012.
  • Accepted in final form January 25, 2013.
  • © 2013 American Academy of Neurology
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Neurology | Print ISSN:0028-3878
Online ISSN:1526-632X

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