Molecular genetic testing for mitochondrial disease: from one generation to the next

Abstract

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.

Fig. 1

Leading indications for referral to Children’s Hospital of Philadelphia Mitochondrial-Genetics Diagnostic Clinic. One hundred and fifty-two participants were evaluated in the outpatient clinical setting between 2008 and 2011, with ages at presentation ranging from 6 weeks to 81 years. Most patients were referred for multiple indications, with the leading referral indications displayed that were present in > 5 % of patients

Fig. 2

Key considerations for pursuing targeted gene capture versus whole exome capture in the clinical diagnostic evaluation of suspected mitochondrial disease. Those factors that may generally be considered a particular advantage for a given approach are circled in red, where the question mark indicates this may be a relative consideration based on the context in which testing is pursued

Fig. 3

A more comprehensive understanding of mitochondrial diseases is obtainable by recognition of molecular genetics etiologies, as emerging next generation sequencing technologies will permit comprehensive genetic analyses to build upon and inform biochemical and clinical definitions of mitochondrial disease