Critically unwell infants and children with mitochondrial disorders diagnosed by ultra-rapid 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 ultra-rapid genomic sequencing

Genet Med. 2024 Oct 14:101293. doi: 10.1016/j.gim.2024.101293. Online ahead of print.

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 ultra-rapid genomic testing as part of a national program.

Methods: Ultra-rapid 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 following broader analysis. Gene-agnostic analysis led to the discovery of two novel disease genes, with pathogenicity validated through targeted functional studies (CRLS1 and MRPL39). Functional studies enabled diagnosis in another four 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: Ultra-rapid 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; Paediatric; Rapid Genomics.