The Australian Genomics Mitochondrial Flagship: A national program delivering mitochondrial diagnoses

Rocio Rius¹, Alison G Compton², Naomi L Baker³, Shanti Balasubramaniam⁴, Stephanie Best⁵, Kaustuv Bhattacharya⁶, Kirsten Boggs⁶, Tiffany Boughtwood⁷, Jeffrey Braithwaite⁸, Drago Bratkovic⁹, Alessandra Bray⁶, Marie-Jo Brion¹⁰, Jo Burke¹¹, Sarah Casauria⁷, Belinda Chong¹², David Coman¹³, Shannon Cowie¹², Mark Cowley¹⁴, Michelle G de Silva², Martin B Delatycki³, Samantha Edwards¹⁵, Carolyn Ellaway¹⁶, Michael C Fahey¹⁷, Keri Finlay⁷, Janice Fletcher¹⁸, Leah E Frajman¹⁹, Ann E Frazier¹⁹, Velimir Gayevskiy²⁰, Roula Ghaoui¹⁸, Himanshu Goel²¹, Ilias Goranitis²², Matilda Haas⁷, Daniella H Hock²³, Denise Howting²⁴, Matilda R Jackson²⁵, Maina P Kava²⁶, Madonna Kemp²⁷, Sarah King-Smith²⁵, Nicole J Lake²⁸, Phillipa J Lamont²⁹, Joy Lee³⁰, Janet C Long⁸, Mandi MacShane²⁴, Evanthia O Madelli⁷, Ellenore M Martin⁶, Justine E Marum³¹, Tessa Mattiske⁷, Jim McGill³², Alejandro Metke²⁷, Sean Murray³³, Julie Panetta¹⁷, Liza K Phillips³⁴, Michael C J Quinn³⁵, Michael T Ryan³⁶, Sarah Schenscher⁹, Cas Simons³⁷, Nicholas Smith³⁸, David A Stroud³⁹, Michel C Tchan⁴⁰, Melanie Tom⁴¹, Mathew Wallis⁴², Tyson L Ware⁴³, AnneMarie E Welch⁴⁴, Christine Wools¹⁷, You Wu⁴⁵, John Christodoulou⁴⁶, David R Thorburn⁴⁷

Affiliations

¹ Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia; Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, NSW, Australia; The University of Melbourne, Melbourne, VIC, Australia.
² The University of Melbourne, Melbourne, VIC, Australia; Murdoch Children's Research Institute, Melbourne, VIC, Australia; Victorian Clinical Genetics Services, Melbourne, VIC, Australia.
³ The University of Melbourne, Melbourne, VIC, Australia; Victorian Clinical Genetics Services, Melbourne, VIC, Australia.
⁴ Sydney Children's Hospitals Network, Westmead, NSW, Australia; University of Sydney, Sydney, NSW, Australia.
⁵ The University of Melbourne, Melbourne, VIC, Australia; Australian Institute of Health Innovation, Macquarie University, Sydney, NSW, Australia; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Victorian Comprehensive Cancer Centre, Melbourne, VIC, Australia; Australian Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
⁶ Sydney Children's Hospitals Network, Westmead, NSW, Australia.
⁷ Australian Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
⁸ Australian Institute of Health Innovation, Macquarie University, Sydney, NSW, Australia.
⁹ Women's and Children's Hospital, Adelaide, SA, Australia.
¹⁰ Australian Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia; QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
¹¹ Tasmanian Clinical Genetics Service, Hobart, Australia; The University of Tasmania, Hobart, TAS, Australia.
¹² Victorian Clinical Genetics Services, Melbourne, VIC, Australia.
¹³ Queensland Children's Hospital, Brisbane, QLD, Australia; Wesley Hospital, Brisbane, QLD, Australia; University of Queensland, Brisbane, QLD, Australia.
¹⁴ Children's Cancer Institute, University of New South Wales, NSW, Australia.
¹⁵ Harry Perkins Institute of Medical Research, University of Western Australia, Perth, WA, Australia.
¹⁶ S1ydney Children's Hospitals Network, Westmead, NSW, Australia; University of Sydney, Sydney, NSW, Australia.
¹⁷ Royal Melbourne Hospital, Melbourne, VIC, Australia.
¹⁸ Royal Adelaide Hospital, Adelaide, SA, Australia.
¹⁹ The University of Melbourne, Melbourne, VIC, Australia; Murdoch Children's Research Institute, Melbourne, VIC, Australia.
²⁰ Garvan Institute of Medical Research, Sydney, NSW, Australia.
²¹ John Hunter Hospital, Newcastle, NSW, Australia.
²² The University of Melbourne, Melbourne, VIC, Australia; Australian Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
²³ The University of Melbourne, Melbourne, VIC, Australia; Bio 21 Molecular Science and Biotechnology Institute, Melbourne, VIC, Australia; Department of Genetic Medicine, Westmead Hospital, Westmead, NSW, Australia.
²⁴ Harry Perkins Institute of Medical Research, Perth, WA, Australia.
²⁵ Australian Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.
²⁶ Perth Children's Hospital, Perth, WA, Australia.
²⁷ The Australian e-Health Research Centre, CSIRO, Brisbane, QLD, Australia.
²⁸ Murdoch Children's Research Institute, Melbourne, VIC, Australia; Yale School of Medicine, New Haven, CT.
²⁹ Perth Children's Hospital, Perth, WA, Australia; Royal Perth Hospital, Perth, WA, Australia.
³⁰ The University of Melbourne, Melbourne, VIC, Australia; Victorian Clinical Genetics Services, Melbourne, VIC, Australia; Royal Children's Hospital, Melbourne, VIC, Australia.
³¹ Victorian Clinical Genetics Services, Melbourne, VIC, Australia; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
³² Queensland Children's Hospital, Brisbane, QLD, Australia.
³³ Mito Foundation, Sydney, NSW, Australia.
³⁴ Mater Hospital, South Brisbane, QLD, Australia.
³⁵ Australian Genomics, Genetic Health Queensland, Brisbane, QLD, Australia.
³⁶ Monash University, Melbourne, VIC, Australia.
³⁷ Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia; Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, NSW, Australia.
³⁸ Department of Neurology and Clinical Neurophysiology, Women's and Children's Hospital, Adelaide, SA, Australia; Discipline of Paediatrics, University of Adelaide, Adelaide, SA, Australia.
³⁹ The University of Melbourne, Melbourne, VIC, Australia; Murdoch Children's Research Institute, Melbourne, VIC, Australia; Victorian Clinical Genetics Services, Melbourne, VIC, Australia; Bio 21 Molecular Science and Biotechnology Institute, Melbourne, VIC, Australia.
⁴⁰ Department of Genetic Medicine, Westmead Hospital, Westmead, NSW, Australia; Faculty of Medicine and Health, University of Sydney, NSW, Australia.
⁴¹ Genetic Health Queensland, Brisbane, QLD, Australia.
⁴² Tasmanian Clinical Genetics Service, Hobart, TAS, Australia; School of Medicine and Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia; Royal Hobart Hospital, Hobart, TAS, Australia.
⁴³ Royal Hobart Hospital, Hobart, TAS, Australia.
⁴⁴ Murdoch Children's Research Institute, Melbourne, VIC, Australia.
⁴⁵ The University of Melbourne, Melbourne, VIC, Australia.
⁴⁶ The University of Melbourne, Melbourne, VIC, Australia; Murdoch Children's Research Institute, Melbourne, VIC, Australia; Victorian Clinical Genetics Services, Melbourne, VIC, Australia. Electronic address: john.christodoulou@mcri.edu.au.
⁴⁷ The University of Melbourne, Melbourne, VIC, Australia; Murdoch Children's Research Institute, Melbourne, VIC, Australia; Victorian Clinical Genetics Services, Melbourne, VIC, Australia. Electronic address: david.thorburn@mcri.edu.au.

PMID: 39305161
DOI: 10.1016/j.gim.2024.101271

The Australian Genomics Mitochondrial Flagship: A national program delivering mitochondrial diagnoses

Rocio Rius et al. Genet Med. 2025 Jan.

. 2025 Jan;27(1):101271.

doi: 10.1016/j.gim.2024.101271. Epub 2024 Sep 19.

Authors

Affiliations

¹ Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia; Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, NSW, Australia; The University of Melbourne, Melbourne, VIC, Australia.
² The University of Melbourne, Melbourne, VIC, Australia; Murdoch Children's Research Institute, Melbourne, VIC, Australia; Victorian Clinical Genetics Services, Melbourne, VIC, Australia.
³ The University of Melbourne, Melbourne, VIC, Australia; Victorian Clinical Genetics Services, Melbourne, VIC, Australia.
⁴ Sydney Children's Hospitals Network, Westmead, NSW, Australia; University of Sydney, Sydney, NSW, Australia.
⁵ The University of Melbourne, Melbourne, VIC, Australia; Australian Institute of Health Innovation, Macquarie University, Sydney, NSW, Australia; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Victorian Comprehensive Cancer Centre, Melbourne, VIC, Australia; Australian Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
⁶ Sydney Children's Hospitals Network, Westmead, NSW, Australia.
⁷ Australian Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
⁸ Australian Institute of Health Innovation, Macquarie University, Sydney, NSW, Australia.
⁹ Women's and Children's Hospital, Adelaide, SA, Australia.
¹⁰ Australian Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia; QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
¹¹ Tasmanian Clinical Genetics Service, Hobart, Australia; The University of Tasmania, Hobart, TAS, Australia.
¹² Victorian Clinical Genetics Services, Melbourne, VIC, Australia.
¹³ Queensland Children's Hospital, Brisbane, QLD, Australia; Wesley Hospital, Brisbane, QLD, Australia; University of Queensland, Brisbane, QLD, Australia.
¹⁴ Children's Cancer Institute, University of New South Wales, NSW, Australia.
¹⁵ Harry Perkins Institute of Medical Research, University of Western Australia, Perth, WA, Australia.
¹⁶ S1ydney Children's Hospitals Network, Westmead, NSW, Australia; University of Sydney, Sydney, NSW, Australia.
¹⁷ Royal Melbourne Hospital, Melbourne, VIC, Australia.
¹⁸ Royal Adelaide Hospital, Adelaide, SA, Australia.
¹⁹ The University of Melbourne, Melbourne, VIC, Australia; Murdoch Children's Research Institute, Melbourne, VIC, Australia.
²⁰ Garvan Institute of Medical Research, Sydney, NSW, Australia.
²¹ John Hunter Hospital, Newcastle, NSW, Australia.
²² The University of Melbourne, Melbourne, VIC, Australia; Australian Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
²³ The University of Melbourne, Melbourne, VIC, Australia; Bio 21 Molecular Science and Biotechnology Institute, Melbourne, VIC, Australia; Department of Genetic Medicine, Westmead Hospital, Westmead, NSW, Australia.
²⁴ Harry Perkins Institute of Medical Research, Perth, WA, Australia.
²⁵ Australian Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.
²⁶ Perth Children's Hospital, Perth, WA, Australia.
²⁷ The Australian e-Health Research Centre, CSIRO, Brisbane, QLD, Australia.
²⁸ Murdoch Children's Research Institute, Melbourne, VIC, Australia; Yale School of Medicine, New Haven, CT.
²⁹ Perth Children's Hospital, Perth, WA, Australia; Royal Perth Hospital, Perth, WA, Australia.
³⁰ The University of Melbourne, Melbourne, VIC, Australia; Victorian Clinical Genetics Services, Melbourne, VIC, Australia; Royal Children's Hospital, Melbourne, VIC, Australia.
³¹ Victorian Clinical Genetics Services, Melbourne, VIC, Australia; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
³² Queensland Children's Hospital, Brisbane, QLD, Australia.
³³ Mito Foundation, Sydney, NSW, Australia.
³⁴ Mater Hospital, South Brisbane, QLD, Australia.
³⁵ Australian Genomics, Genetic Health Queensland, Brisbane, QLD, Australia.
³⁶ Monash University, Melbourne, VIC, Australia.
³⁷ Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia; Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, NSW, Australia.
³⁸ Department of Neurology and Clinical Neurophysiology, Women's and Children's Hospital, Adelaide, SA, Australia; Discipline of Paediatrics, University of Adelaide, Adelaide, SA, Australia.
³⁹ The University of Melbourne, Melbourne, VIC, Australia; Murdoch Children's Research Institute, Melbourne, VIC, Australia; Victorian Clinical Genetics Services, Melbourne, VIC, Australia; Bio 21 Molecular Science and Biotechnology Institute, Melbourne, VIC, Australia.
⁴⁰ Department of Genetic Medicine, Westmead Hospital, Westmead, NSW, Australia; Faculty of Medicine and Health, University of Sydney, NSW, Australia.
⁴¹ Genetic Health Queensland, Brisbane, QLD, Australia.
⁴² Tasmanian Clinical Genetics Service, Hobart, TAS, Australia; School of Medicine and Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia; Royal Hobart Hospital, Hobart, TAS, Australia.
⁴³ Royal Hobart Hospital, Hobart, TAS, Australia.
⁴⁴ Murdoch Children's Research Institute, Melbourne, VIC, Australia.
⁴⁵ The University of Melbourne, Melbourne, VIC, Australia.
⁴⁶ The University of Melbourne, Melbourne, VIC, Australia; Murdoch Children's Research Institute, Melbourne, VIC, Australia; Victorian Clinical Genetics Services, Melbourne, VIC, Australia. Electronic address: john.christodoulou@mcri.edu.au.
⁴⁷ The University of Melbourne, Melbourne, VIC, Australia; Murdoch Children's Research Institute, Melbourne, VIC, Australia; Victorian Clinical Genetics Services, Melbourne, VIC, Australia. Electronic address: david.thorburn@mcri.edu.au.

PMID: 39305161
DOI: 10.1016/j.gim.2024.101271

Abstract

Purpose: Families living with mitochondrial diseases (MD) often endure prolonged diagnostic journeys and invasive testing, yet many remain without a molecular diagnosis. The Australian Genomics Mitochondrial Flagship, comprising clinicians, diagnostic, and research scientists, conducted a prospective national study to identify the diagnostic utility of singleton genomic sequencing using blood samples.

Methods: A total of 140 children and adults living with suspected MD were recruited using modified Nijmegen criteria (MNC) and randomized to either exome + mitochondrial DNA (mtDNA) sequencing or genome sequencing.

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 etiology was identified in 77% of diagnoses, irrespective of disease onset. Diagnostic rates were higher in pediatric-onset (71%) than adult-onset (31%) cases and comparable in children with non-European (78%) vs European (67%) ancestry. For children, higher MNC scores correlated with increased diagnostic yield and fewer diagnoses in phenocopy genes. Additionally, 3 adult patients had a mtDNA deletion discovered in skeletal muscle that was not initially identified 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.

Keywords: Diagnosis; Diagnostic Yield; Genomics; Mitochondrial Disease; Proteomics.

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Conflict of interest statement

Conflict of Interest John Christodoulou is an approved pathology provider for Victorian Clinical Genetics Services.

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The Australian Genomics Mitochondrial Flagship: A national program delivering mitochondrial diagnoses

Affiliations

The Australian Genomics Mitochondrial Flagship: A national program delivering mitochondrial diagnoses

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical