Major cause of rare genetic mitochondrial disease identified

July 09, 2020

Research at a Glance: A cutting-edge study from the Murdoch Children's Research Institute (MCRI) has given hope to families of children born with a fatal heart muscle disease caused by faulty cell machinery.

The research, published in Med, a new journal from Cell Press, has found disruptions in the ATAD3 gene cluster caused fatal heart failure soon after birth. But because the gene cluster disruptions arose spontaneously, parents have a low risk of having further children with the same disease.

Mistakes in any one of around 350 genes can cause mitochondria, the powerplants inside our cells, to fail. This results in what are collectively called mitochondrial diseases, severely affecting at least one in 5000 people.

Often fatal, mitochondrial diseases can affect single organs or whole-body systems resulting in a spectrum of symptoms and syndromes. Because these diseases are caused by genetic errors, there is no cure. Existing treatments do not delay disease progression and most children with mitochondrial disease die before adulthood.

By carefully re-examining genomic data from 17 babies from families in Australia, Japan, New Zealand and the Netherlands, the new research, led by Professor David Thorburn and other senior MCRI genetics researchers, has confirmed ATAD3 as the most common cause of lethal mitochondrial disease soon after birth.

Professor Thorburn said, "The ATAD3 gene cluster lies within a genetic region where repeating DNA letters complicate even the latest genomic diagnosis methods. This explains why standard genetic screens have missed ATAD3 mutations in the past."

"Using a combination of advanced gene and protein technologies, our team has shown that ATAD3 genes can be mistakenly copied and pasted next to themselves. These duplications create a faulty protein that disrupts normal ATAD3 function, sadly resulting in fatal heart failure around the time of birth."

"What's exciting for families involved in this study is that we have given them the confidence to plan for another baby, knowing that yes, they may have experienced some awful luck, but that it has an extremely low chance of happening again" said Professor Thorburn.

The team from MCRI and the Victorian Clinical Genetics Services (VCGS; which validated the diagnostic test) plans to re-analyse previously collected genetic data from families whose children died with similar unexplained symptoms. One of the "cold cases" described in the current study was of a family whose child died over 20 years ago.

MCRI Professor John Christodoulou who co-led the study, said, "Crucially, the study provides insight into the still unknown role of ATAD3 in the fatal disease, and highlights the importance of continual improvement in our screening capabilities."

"It also shows the importance of collecting and storing these samples. We might not have the technology or the insights to diagnose every genetic disease yet, but we are constantly making these incremental advances and providing answers to our families, even years or decades later. Their invaluable contribution means another family may be spared the same pain."
Publication: Fatal perinatal mitochondrial cardiac failure caused by recurrent de novo duplications in the ATAD3 locus. Med. DOI:

Available for interview:
Professor David Thorburn,
Leader Brain and Mitochondrial Disease Research Group MCRI
Honorary Professorial Fellow, Department of Paediatrics, The University of Melbourne

Australian family affected by ATAD3

Media Contact:
Bridie Byrne
MCRI communications specialist

About MCRI

The Murdoch Children's Research Institute (MCRI) is the largest child health research institute in Australia committed to making discoveries and developing treatments to improve child and adolescent health in Australia and around the world. MCRI pioneers new treatments, trials better vaccines and improves ways of diagnosing and helping sick babies, children and adolescents. MCRI is one of the only research institutes in Australia to offer genetic testing to find answers for families of children with previously undiagnosed conditions.


The research was supported by grants and fellowships from the Australian National Health and Medical Research Council (NHMRC) [1164479; 1155244; 1068278; 1140851], the US Department of Defense Congressionally Directed Medical Research Programs PR170396, the New South Wales Office of Health and Medical Research Council Sydney Genomics Collaborative grant, the Victorian Government's Operational Infrastructure Support Program, the Australian Mito Foundation, the National Council on Science and Technology (CONACYT), the Vincent Chiodo Charitable Trust, the Angela Wright Bennett Foundation, the McCusker Charitable Foundation, the US National Institutes of Health R35GM122455, the Howard Hughes Medical Institute Investigator Program and the Australian Genomics Health Alliance, which is funded by the NHMRC (1113531) and the Medical Research Future Fund. This work was supported in part by the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development, AMED (19ek0109273, 18ek0109177), the Program for an Integrated Database of Clinical and Genomic Information from AMED (19kk0205014, 18kk0205002), MEXT-Supported Program for the Private University Research Branding Project, the Japan Society for the Promotion of Science (JSPS) KAKENHI 19H03624 (Grant-in-Aid for Scientific Research (B)). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS.

*The content of this communication is the sole responsibility of MCRI and does not reflect the views of the NHMRC or other funding bodies


Researchers from around the world contributed to the study. This included: Juntendo University; Bio21 Molecular Science and Biotechnology Institute, University of Melbourne; Monash Biomedicine Discovery Institute; National Center for Global Health and Medicine; Victorian Clinical Genetics Services; Yale School of Medicine; Australian Genome Research Facility; Saitama Medical University Hospital; Chiba Children's Hospital; Hudson Institute of Medical Research; Monash Children's Hospital; Vrije Universiteit and Amsterdam Neuroscience, Amsterdam University Medical Center; Maastricht University Medical Center; University of Otago; SA Pathology; PathWest Laboratory Medicine Western Australia; Genetic Services of Western Australia and King Edward Memorial Hospital for Women Perth; Telethon Kids Institute; The University of Western Australia; The Children's Hospital at Westmead; University of Sydney; The Canberra Hospital; Illumina, Inc; Children's Cancer Institute; Garvan Institute of Medical Research; Broad Institute; Institute for Molecular Bioscience, The University of Queensland.

Murdoch Childrens Research Institute

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