David R. Thorburn^1,2,3
1Murdoch Children’s Research Institute, Melbourne, Australia

 ²University of Melbourne, Parkville, Australia 

³Victorian Clinical Genetics Services, Melbourne, Australia

In patients suspected of mitochondrial disease, a “genomics first” approach has largely replaced traditional enzyme and histochemical testing. Reported genomic diagnostic yields are typically 30-60% but depend on both the methods used and recruitment criteria. For example, our recent Australian Genomics Mito Flagship national study included 140 probands with pediatric- or adult-onset suspected mitochondrial disease . Initial sequencing used blood DNA. Proteomic or other follow-up analyses were performed when feasible. Overall diagnostic yield was 55%, but higher in paediatric-onset (71%) than adult-onset (31%) cases. 29% of diagnoses were in non-mito genes (mito mimics). These findings reflect the broad clinical features of mito that overlap hundreds of other conditions, along with ascertainment bias and loss of some mtDNA variants from blood in adults. 

MitoMDT is an MRFF-funded national study recruiting families with suspected mitochondrial disease to apply multi-Omic technologies seeking to improve overall diagnostic rates to over 70%. It combines researchers, clinicians and lab experts from around Australia with expertise in mitochondrial disease, genomics, transcriptomics, quantitative proteomics, metabolomics, computational biology and targeted functional testing. Initial results have provided evidence to upgrade VUS in multiple genes to Likely Pathogenic or Pathogenic as well as validating a novel disease gene.