Sequencing Analysis Optimized for Mitochondrial Disease

A study team, headed by a specialist in mitochondrial medicine at The Children's Hospital of Philadelphia (CHOP; PA, USA), developed a one-step, off-the-shelf tool that analyzes both nuclear and mitochondrial DNA to help evaluate the genetic cause of suspected mitochondrial disease. The scientists examined the performance characteristics of a custom Agilent Technologies (Santa Clara, CA, USA) whole-exome capture that they designed to facilitate simultaneous analysis of the standard 50 megabases (Mb) whole exome with optimized coverage of the complete MitoCarta nuclear gene set and the mitochondrial DNA (mtDNA) genome. MitoCarta is a collection of 1,013 nuclear and mtDNA genes-encoding proteins.

This platform, called the "1:1000 Mito-Plus Whole-Exome" kit, provides a potential one-stop whole exome sequencing (WES) solution that can be applied to both research and clinical genetic diagnostic evaluations of individuals with suspected mitochondrial disease. The customized kit has the sensitivity to detect mitochondrial genome mutations present at levels as low as 8% compared to conventional gene sequencing, which can detect only heteroplasmic mutations that reach levels of at least 30% to 50%. The team confirmed definite mitochondrial disease in 16% of patients and excluded primary mitochondrial disease in 9%.

Marni J. Falk, MD, the director and attending physician in the Mitochondrial-Genetic Disease Clinic at CHOP, said, "Before 2005, very few individuals could receive definitive molecular diagnoses for mitochondrial diseases, because of limitations in both knowledge and technology. Since that time, the clinical ability to sequence whole mitochondrial DNA genomes has significantly improved the diagnosis of many mitochondrial disorders." Dr. Falk added, "Molecular genetics is yielding a more nuanced understanding of the cellular pathways underlying symptoms in many mitochondrial disorders. Those pathways offer potential new targets for treating these disorders." The study was published on December 26, 2012, in the journal Discovery Medicine.

Related Links:
The Children's Hospital of Philadelphia
Agilent Technologies
American Cancer Society