Exome sequencing of a patient with suspected mitochondrial disease reveals a likely multigenic etiology

BMC Med Genet. 2013 Aug 16;14:83. doi: 10.1186/1471-2350-14-83.


Background: The clinical features of mitochondrial disease are complex and highly variable, leading to challenges in establishing a specific diagnosis. Despite being one of the most commonly occurring inherited genetic diseases with an incidence of 1/5000, ~90% of these complex patients remain without a DNA-based diagnosis. We report our efforts to identify the pathogenetic cause for a patient with typical features of mitochondrial disease including infantile cataracts, CPEO, ptosis, progressive distal muscle weakness, and ataxia who carried a diagnosis of mitochondrial disease for over a decade.

Methods: Whole exome sequencing and bioinformatic analysis of these data were conducted on the proband.

Results: Exome sequencing studies showed a homozygous splice site mutation in SETX, which is known to cause Spinocerebellar Ataxia, Autosomal Recessive 1 (SCAR1). Additionally a missense mutation was identified in a highly conserved position of the OCRL gene, which causes Lowe Syndrome and Dent Disease 2.

Conclusions: This patient's complex phenotype reflects a complex genetic etiology in which no single gene explained the complete clinical presentation. These genetic studies reveal that this patient does not have mitochondrial disease but rather a genocopy caused by more than one mutant locus. This study demonstrates the benefit of exome sequencing in providing molecular diagnosis to individuals with complex clinical presentations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Computational Biology
  • DNA Helicases
  • Exome*
  • Genetic Diseases, X-Linked / genetics
  • Genetic Loci
  • Homozygote
  • Humans
  • Male
  • Mitochondrial Diseases / diagnosis
  • Mitochondrial Diseases / genetics*
  • Multifunctional Enzymes
  • Mutation, Missense
  • Nephrolithiasis / genetics
  • Oculocerebrorenal Syndrome / genetics
  • Pedigree
  • Phenotype
  • Phosphoric Monoester Hydrolases / genetics
  • RNA Helicases / genetics*
  • RNA, Ribosomal, 16S / isolation & purification
  • Sequence Analysis, DNA / methods*
  • Spinocerebellar Ataxias / congenital
  • Spinocerebellar Degenerations / genetics


  • Multifunctional Enzymes
  • RNA, Ribosomal, 16S
  • Phosphoric Monoester Hydrolases
  • OCRL protein, human
  • SETX protein, human
  • DNA Helicases
  • RNA Helicases

Supplementary concepts

  • Dent Disease 2
  • Spinocerebellar ataxia, autosomal recessive 1