title: Targeted exome sequencing of suspected mitochondrial disorders.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Lieber
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Calvo
authors.forename: Kristy
authors.initials: K
authors.lastname: Shanahan
authors.forename: Nancy G
authors.initials: NG
authors.lastname: Slate
authors.forename: Shangtao
authors.initials: S
authors.lastname: Liu
authors.forename: Steven G
authors.initials: SG
authors.lastname: Hershman
authors.forename: Nina B
authors.initials: NB
authors.lastname: Gold
authors.forename: Brad A
authors.initials: BA
authors.lastname: Chapman
authors.forename: David R
authors.initials: DR
authors.lastname: Thorburn
authors.forename: Gerard T
authors.initials: GT
authors.lastname: Berry
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Schmahmann
authors.forename: Mark L
authors.initials: ML
authors.lastname: Borowsky
authors.forename: David M
authors.initials: DM
authors.lastname: Mueller
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Sims
authors.forename: Vamsi K
authors.initials: VK
authors.lastname: Mootha
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D004272:DNA, Mitochondrial / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D018390:Gene Targeting / Q000379:methods*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000175:diagnosis* / Q000235:genetics*; D008969:Molecular Sequence Data; D010375:Pedigree; D017422:Sequence Analysis, DNA / Q000379:methods*; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial