Critically unwell infants and children with mitochondrial disorders diagnosed by ultrarapid genomic sequencing

Megan Ball; Sophie E Bouffler; Christopher B Barnett; Mary-Louise Freckmann; Matthew F Hunter; Benjamin Kamien; Karin S Kassahn; Sebastian Lunke; Chirag V Patel; Jason Pinner; Tony Roscioli; Sarah A Sandaradura; Hamish S Scott; Tiong Y Tan; Mathew Wallis; Alison G Compton; David R Thorburn; Zornitza Stark; John Christodoulou

doi:10.1016/j.gim.2024.101293

Critically unwell infants and children with mitochondrial disorders diagnosed by ultrarapid genomic sequencing

Genet Med. 2025 Jan;27(1):101293. doi: 10.1016/j.gim.2024.101293. Epub 2024 Oct 15.

Authors

Megan Ball¹, Sophie E Bouffler², Christopher B Barnett³, Mary-Louise Freckmann⁴, Matthew F Hunter⁵, Benjamin Kamien⁶, Karin S Kassahn⁷, Sebastian Lunke⁸, Chirag V Patel⁹, Jason Pinner¹⁰, Tony Roscioli¹¹, Sarah A Sandaradura¹², Hamish S Scott¹³, Tiong Y Tan¹⁴, Mathew Wallis¹⁵, Alison G Compton¹⁶, David R Thorburn¹⁶, Zornitza Stark¹⁷, John Christodoulou¹⁸

Affiliations

¹ Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia; Royal Children's Hospital, Melbourne, Australia; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia. Electronic address: megan.ball@mcri.edu.au.
² Australian Genomics, Melbourne, Australia.
³ Paediatric and Reproductive Genetics Unit, Women's and Children's Hospital, North Adelaide, Australia; Adelaide Medical School, The University of Adelaide, Adelaide, Australia.
⁴ Department of Clinical Genetics, The Canberra Hospital, Canberra, Australia.
⁵ Monash Genetics, Monash Health, Melbourne, Australia; Department of Paediatrics, Monash University, Melbourne, Australia.
⁶ Genetic Services of Western Australia, Perth, Australia.
⁷ Adelaide Medical School, The University of Adelaide, Adelaide, Australia; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia.
⁸ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia; Australian Genomics, Melbourne, Australia.
⁹ Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Australia.
¹⁰ Sydney Children's Hospitals Network - Randwick, Sydney, Australia; University of New South Wales, Sydney, New South Wales, Australia.
¹¹ NSW Health Pathology Randwick Genomics Laboratory, Sydney, Australia; Euroscience Research Australia, University of New South Wales, Sydney, Australia.
¹² Sydney Children's Hospitals Network-Westmead, Sydney, Australia; University of Sydney, Sydney, Australia.
¹³ Australian Genomics, Melbourne, Australia; Adelaide Medical School, The University of Adelaide, Adelaide, Australia; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia; Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, Australia; UniSA Clinical and Health Sciences, University of South Australia, Adelaide, Australia.
¹⁴ Department of Paediatrics, University of Melbourne, Melbourne, Australia; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia.
¹⁵ Tasmanian Clinical Genetics Service, Tasmanian Health Service, Hobart, Australia; School of Medicine and Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.
¹⁶ Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia.
¹⁷ Department of Paediatrics, University of Melbourne, Melbourne, Australia; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia; Australian Genomics, Melbourne, Australia.
¹⁸ Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia; Australian Genomics, Melbourne, Australia. Electronic address: john.christodoulou@mcri.edu.au.

PMID: 39417332
DOI: 10.1016/j.gim.2024.101293

Abstract

Purpose: To characterize the diagnostic and clinical outcomes of a cohort of critically ill infants and children with suspected mitochondrial disorders (MD) undergoing ultrarapid genomic testing as part of a national program.

Methods: Ultrarapid genomic sequencing was performed in 454 families (genome sequencing: n = 290, exome sequencing +/- mitochondrial DNA sequencing: n = 164). In 91 individuals, MD was considered, prompting analysis using an MD virtual gene panel. These individuals were reviewed retrospectively and scored according to modified Nijmegen Mitochondrial Disease Criteria.

Results: A diagnosis was achieved in 47% (43/91) of individuals, 40% (17/43) of whom had an MD. Seven additional individuals in whom an MD was not suspected were diagnosed with an MD after broader analysis. Gene-agnostic analysis led to the discovery of 2 novel disease genes, with pathogenicity validated through targeted functional studies (CRLS1 and MRPL39). Functional studies enabled diagnosis in another 4 individuals. Of the 24 individuals ultimately diagnosed with an MD, 79% had a change in management, which included 53% whose care was redirected to palliation.

Conclusion: Ultrarapid genetic diagnosis of MD in acutely unwell infants and children is critical for guiding decisions about the need for additional investigations and clinical management.

Keywords: Mitochondrial disorders; Neonatal; Pediatric; Rapid Genomics.

MeSH terms

Child
Child, Preschool
Critical Illness*
DNA, Mitochondrial / genetics
Exome Sequencing
Female
Genetic Testing / methods
Genomics / methods
High-Throughput Nucleotide Sequencing
Humans
Infant
Infant, Newborn
Male
Mitochondrial Diseases* / diagnosis
Mitochondrial Diseases* / genetics
Mutation / genetics
Retrospective Studies

Substances

DNA, Mitochondrial