ORIGINAL ARTICLE
Next-generation sequencing for mitochondrial diseases: A wide diagnostic spectrum
Valeria Vasta, J Lawrence Merritt II,
Russell P. Saneto,
Si Houn Hahn,
J Lawrence Merritt II
Department of Pediatrics, Division of Genetic Medicine, University of Washington School of Medicine/Seattle Children's Hospital
Search for more papers by this authorRussell P. Saneto
Department of Neurology, Division of Pediatric Neurology, University of Washington School of Medicine/ Seattle Children's Hospital, Seattle, WA, USA
Search for more papers by this authorCorresponding Author
Si Houn Hahn
Seattle Children's Hospital Research Institute
Department of Pediatrics, Division of Genetic Medicine, University of Washington School of Medicine/Seattle Children's Hospital
Si Houn Hahn, MD PhD, Department of Pediatrics, University of Washington School of Medicine, Seattle Children's Research Institute, C9S, 1900 9th Avenue, Seattle, WA 98101, USA. Email: [email protected]Search for more papers by this authorValeria Vasta, J Lawrence Merritt II,
Russell P. Saneto,
Si Houn Hahn,
J Lawrence Merritt II
Department of Pediatrics, Division of Genetic Medicine, University of Washington School of Medicine/Seattle Children's Hospital
Search for more papers by this authorRussell P. Saneto
Department of Neurology, Division of Pediatric Neurology, University of Washington School of Medicine/ Seattle Children's Hospital, Seattle, WA, USA
Search for more papers by this authorCorresponding Author
Si Houn Hahn
Seattle Children's Hospital Research Institute
Department of Pediatrics, Division of Genetic Medicine, University of Washington School of Medicine/Seattle Children's Hospital
Si Houn Hahn, MD PhD, Department of Pediatrics, University of Washington School of Medicine, Seattle Children's Research Institute, C9S, 1900 9th Avenue, Seattle, WA 98101, USA. Email: [email protected]Search for more papers by this authorAbstract
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.
Supporting Information
Table S1. List of targeted genes.
| Filename | Description |
|---|---|
| ped3644_sm_TableS1.doc68 KB | Supporting info item |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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