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https://hdl.handle.net/2440/69865
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Type: | Journal article |
Title: | Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing |
Author: | Calvo, S. Compton, A. Hershman, S. Lim, S. Lieber, D. Tucker, E. Laskowski, A. Garone, C. Liu, S. Jaffe, D. Christodoulou, J. Fletcher, J. Bruno, D. Goldblatt, J. DiMauro, S. Thorburn, D. Mootha, V. |
Citation: | Science Translational Medicine, 2012; 4(118):1-15 |
Publisher: | American Association for the Advancement of Science |
Issue Date: | 2012 |
ISSN: | 1946-6234 1946-6242 |
Statement of Responsibility: | Sarah E. Calvo, Alison G. Compton, Steven G. Hershman, Sze Chern Lim, Daniel S. Lieber, Elena J. Tucker, Adrienne Laskowski, Caterina Garone, Shangtao Liu, David B. Jaffe, John Christodoulou, Janice M. Fletcher, Damien L. Bruno, Jack Goldblatt, Salvatore DiMauro, David R. Thorburn, Vamsi K. Mootha |
Abstract: | Advances in next-generation sequencing (NGS) promise to facilitate diagnosis of inherited disorders. Although in research settings NGS has pinpointed causal alleles using segregation in large families, the key challenge for clinical diagnosis is application to single individuals. To explore its diagnostic use, we performed targeted NGS in 42 unrelated infants with clinical and biochemical evidence of mitochondrial oxidative phosphorylation disease. These devastating mitochondrial disorders are characterized by phenotypic and genetic heterogeneity, with more than 100 causal genes identified to date. We performed "MitoExome" sequencing of the mitochondrial DNA (mtDNA) and exons of ~1000 nuclear genes encoding mitochondrial proteins and prioritized rare mutations predicted to disrupt function. Because patients and healthy control individuals harbored a comparable number of such heterozygous alleles, we could not prioritize dominant-acting genes. However, patients showed a fivefold enrichment of genes with two such mutations that could underlie recessive disease. In total, 23 of 42 (55%) patients harbored such recessive genes or pathogenic mtDNA variants. Firm diagnoses were enabled in 10 patients (24%) who had mutations in genes previously linked to disease. Thirteen patients (31%) had mutations in nuclear genes not previously linked to disease. The pathogenicity of two such genes, NDUFB3 and AGK, was supported by complementation studies and evidence from multiple patients, respectively. The results underscore the potential and challenges of deploying NGS in clinical settings. |
Keywords: | Cell Nucleus Fibroblasts Humans Mitochondrial Myopathies Mitochondrial Diseases Electron Transport Complex I Phosphotransferases (Alcohol Group Acceptor) DNA, Mitochondrial Case-Control Studies Reproducibility of Results Sequence Analysis, DNA Amino Acid Sequence Base Sequence Oxidative Phosphorylation Mutation Molecular Sequence Data Child Child, Preschool Infant Infant, Newborn Female Male Genes, Mitochondrial Genetic Association Studies Exome |
Rights: | Copyright © 2012, American Association for the Advancement of Science |
DOI: | 10.1126/scitranslmed.3003310 |
Published version: | http://dx.doi.org/10.1126/scitranslmed.3003310 |
Appears in Collections: | Aurora harvest 5 Paediatrics publications |
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