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Sequencing-based diagnosis of mitochondrial disease

Analysis of a study published in a science journal   |   By Dr Sowmiya Moorthie   |   Published 30 January 2012
Study: Molecular Diagnosis of Infantile Mitochondrial Disease with Targeted Next-Generation Sequencin
By: Calvo S.E. et al. (17 authors total)
In: Science Translational Medicine
What this study set out to do:

Evaluate the use of next-generation sequencing (NGS) technologies for clinical diagnosis of genetic diseases for which the exact genes involved and mode of inheritance and are uncertain.

How they went about it:

Human oxidative phosphorylation (OXPHOS) disease, which is clinically variable in presentation and can be caused by mutations in a number of mitochondrial or nuclear genes, was used as an exemplar. 42 children who showed clinical and biochemical evidence of OXPHOS were selected and exome sequencing of mitochondrial DNA and 1034 nuclear genes involved in mitochondrial function was performed. Causal variants were identified through comparison with databases that recorded genetic variation in healthy individuals.


Ten patients had mutations in causal (known disease-associated) genes and could be given a molecular diagnosis. A further thirteen patients has mutations in candidate (potentially disease-associated) genes, but the pathogenicity of these mutations is yet to be established. The study was not able to identify causal or candidates genes for the remaining patients. This may be due to a number of factors including an incomplete understanding of the molecular basis of the disease.


The pilot study shows the value of using NGS methods achieve a molecular diagnosis for those diseases which are not amenable to traditional sequencing methods. The use of these methods and its integration with biochemical and clinical knowledge can lead to improvements in care and treatment of these patients.   

Our view:

NGS technologies can help diagnose some genetically and medically variable conditions, but the inability to achieve a molecular diagnosis for many of the patients also highlights some of the issues faced in the identification and clinical interpretation of genetic variants identified by sequencing. Often further work is needed to validate and assess their pathogenicity.

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