The Australian Genomics Mitochondrial Flagship: A National Program Delivering Mitochondrial Diagnoses

Purpose. Families living with mitochondrial diseases (MD) often endure prolonged diagnostic journeys and invasive testing, yet many remain without a molecular diagnosis. Through a national team of clinicians, diagnostic, and research scientists, the Australian Genomics Mitochondrial disease flagship conducted a prospective study to identify the diagnostic utility of singleton genomic sequencing using blood samples as a first step to diagnose MD. Methods. 140 children and adults living with suspected MD were recruited using modified Nijmegen criteria (MNC) and randomised to either exome + mtDNA sequencing (ES+mtDNAseq) or genome sequencing (GS). Results. Diagnostic yield was 55% (n=77) with variants in nuclear (n=37) and mtDNA (n=18) MD genes, as well as phenocopy genes (n=22). A nuclear gene aetiology was identified in 77% of diagnoses, irrespective of disease onset. Diagnostic rate was higher in paediatric-onset (71%) than adult-onset (31%) cases. For children, higher MNC scores correlated with increased diagnostic yield and fewer diagnoses in phenocopy genes. Additionally, three adult patients had a mtDNA deletion discovered in skeletal muscle that was not initially detected in blood. Conclusion. Genomic sequencing from blood can simplify the diagnostic pathway for individuals living with suspected MD, especially those with childhood onset diseases and high MNC scores. ### Competing Interest Statement JC is an approved pathology provider for the Victorian Clinical Genetics Service. The rest of authors declare no conflict of interest. ### Funding Statement The Mitochondrial Flagship project was funded by Australian Genomics Health Alliance (Australian Genomics) NHMRC Targeted Call for Research grant GNT1113531 and supported by NHMRC grants 1164479, 1155244, 1159456, and 2009732, and the US Department of Defense Congressionally Directed Medical Research Programs PR170396. We acknowledge the Australian Mito Foundation for funding support. We are grateful to the Crane, Perkins, and Miller families for their generous financial support. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was conducted in accordance with the revised Declaration of Helsinki and following the Australian National Health and Medical Research Council statement of ethical conduct in research involving humans. The Mitochondrial Flagship study was reviewed and approved through our lead Human Research Ethics Committee (HREC), Royal Melbourne Hospital (formerly known as Melbourne Health) (HREC/16/MH/251). Sites that were not covered at the time by the Australian National Mutual Acceptance system were reviewed and approved by the Western Australian Child and Adolescent Health Service HREC (RGS0000000086), Tasmanian HREC (H0016443) and Queensland UnitingCare Health HREC (1717). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The datasets supporting the current study have not been deposited in a public repository due to consent restrictions. De-identified genomic and associated data from this study are available for ethically approved research. The online access application process is administered by the Australian Genomics Data Access Committee.