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.