Next-generation sequencing for mitochondrial diseases: a wide diagnostic spectrum

Pediatr Int. 2012 Oct;54(5):585-601. doi: 10.1111/j.1442-200X.2012.03644.x. Epub 2012 Jul 10.


Background: The current diagnostic approach for mitochondrial disorders requires invasive procedures such as muscle biopsy and multiple biochemical testing but the results are often inconclusive. Clinical sequencing tests are available only for a limited number of genes. Recently, massively parallel sequencing has become a powerful tool for testing genetically heterogeneous conditions such as mitochondrial disorders.

Methods: Targeted next-generation sequencing was performed on 26 patients with known or suspected mitochondrial disorders using in-solution capture for the exons of 908 known and candidate nuclear genes and an Illumina genome analyzer.

Results: None of the 18 patients with various abnormal respiratory chain complex (RCC) activities had molecular defects in either subunits or assembly factors of mitochondrial RCC enzymes except a reference control sample with known mutations in SURF1. Instead, several variants in known pathogenic genes including CPT2, POLG, PDSS1, UBE3A, SDHD, and a few potentially pathogenic variants in candidate genes such as MTO1 or SCL7A13 were identified.

Conclusions: Sequencing only nuclear genes for RCC subunits and assembly factors may not provide the diagnostic answers for suspected patients with mitochondrial disorders. The present findings indicate that the diagnostic spectrum of mitochondrial disorders is much broader than previously thought, which could potentially lead to misdiagnosis and/or inappropriate treatment. Overall analytic sensitivity and precision appear acceptable for clinical testing. Despite the limitations in finding mutations in all patients, the present findings underscore the considerable clinical benefits of targeted next-generation sequencing and serve as a prototype for extending the clinical evaluation in this clinically heterogeneous patient group.

MeSH terms

  • Base Sequence
  • Child
  • Child, Preschool
  • Electron Transport / genetics*
  • Female
  • High-Throughput Nucleotide Sequencing / methods*
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Mitochondrial Diseases / diagnosis*
  • Mitochondrial Diseases / genetics
  • Mutation
  • Sequence Analysis, DNA / methods*