, Volume 10, Issue 2, pp 251–261 | Cite as

Molecular Genetic Testing for Mitochondrial Disease: From One Generation to the Next

  • Elizabeth McCormick
  • Emily Place
  • Marni J. Falk


Molecular genetic diagnostic testing for mitochondrial disease has evolved continually since the first genetic basis for a clinical mitochondrial disease syndrome was identified in the late 1980s. Owing to global limitations in both knowledge and technology, few individuals, even among those with strong clinical or biochemical evidence of mitochondrial respiratory chain dysfunction, ever received a definitive molecular diagnosis prior to 2005. Clinically available genetic diagnostic testing options improved by 2006 to include sequencing and deletion analysis of an increasing number of individual nuclear genes linked to mitochondrial disease, genome-wide microarray analysis for chromosomal copy number abnormalities, and mitochondrial DNA whole genome sequence analysis. To assess the collective effect of these tests on the genetic diagnosis of suspected mitochondrial disease, we report here results from a retrospective review of the diagnostic yield in patients evaluated from 2008 to 2011 in the Mitochondrial-Genetics Diagnostic Clinic at The Children’s Hospital of Philadelphia. Among 152 patients aged 6 weeks to 81 years referred for clinical evaluation of multisystem presentations concerning for suspected mitochondrial disease, a genetic etiology was established that confirmed definite mitochondrial disease in 16.4 % and excluded primary mitochondrial disease in 9.2 %. Substantial diagnostic challenges remain owing to the clinical difficulty and frank low yield of a priori selecting individual nuclear genes to sequence based on particular symptomatic or biochemical manifestations of suspected mitochondrial disease. These findings highlight the particular utility of massively parallel nuclear exome sequencing technologies, whose benefits and limitations are explored relative to the clinical genetic diagnostic evaluation of mitochondrial disease.

Key Words

Next generation sequencing massively parallel sequencing whole exome sequencing retrospective study mitochondrial disease diagnosis 



We thank the many patients and families who contributed to this work, as well as the many clinicians who contributed to the multispecialty evaluations and care of these patients. This work was funded, in part, by a grant from the National Institutes of Health (R03-DK082446 to M.J.F.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The content of the article has not been influenced by the sponsors.

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Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2012

Authors and Affiliations

  • Elizabeth McCormick
    • 1
  • Emily Place
    • 1
    • 2
  • Marni J. Falk
    • 1
  1. 1.Divisions of Human Genetics and Child Development and Metabolic Disease, Department of PediatricsThe Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of MedicinePhiladelphiaUSA
  2. 2.Department of Ophthalmology, Ocular Genomics Institute, Massachusetts Eye and Ear InfirmaryHarvard Medical SchoolBostonUSA

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