Rapid mitochondrial genome (MTDNA) sequencing: facilitating rapid diagnosis of mitochondrial diseases in paediatric acute care.

Objective: While standard rapid genomic testing techniques analyse nuclear DNA variants using whole exome (WES) and/or whole genome (WGS) sequencing, rapid mtDNA analysis is not usually performed. We describe our experience using rapid mtDNA sequencing in tandem with WES in the Australian Genomics Acute Care Genomics flagship. Method(s): Two infants presenting with persistent lactic acidosis and bone marrow failure were recruited for rapid genomic testing. With clinical suspicion of mitochondrial disease, both infants underwent rapid WES and mtDNA sequencing in tandem, the latter using Nextera libraries from a full length mtDNA amplicon. Result(s): WES was non-diagnostic. mtDNA sequencing identified a single large-scale mtDNA deletion in both infants, consistent with Pearson syndrome (MIM 557000). Diagnostic reports were issued within 73 hours 55 minutes and 54 hours 25 minutes, respectively. Both infants avoided invasive bone marrow biopsies and a range of other investigations. Conclusion(s): Rapid mtDNA sequencing in tandem with WES Results in additional diagnoses in seriously ill children with suspected mitochondrial disease, suggesting that WES alone may be insufficient in this setting. When designing rapid genomic diagnostic programs, centres should consider mtDNA analysis, combining WES and mtDNA sequencing in tandem, or analysing mtDNA data from WGS, which captures the mitochondrial genome.Copyright © 2018