Lisa G Riley1,2, Mark J Cowley3,4, Velimir Gayevskiy3, Andre E Minoche3, Clare Puttick3, David R Thorburn5,6,7, Rocio Rius5, Alison G Compton5, Minal J Menezes8,9, Kaustuv Bhattacharya9,10, David Coman11,12,13, Carolyn Ellaway9,10,14, Ian E Alexander9,10, Louisa Adams9,10,14, Maina Kava15,16,17, Jacqui Robinson18, Carolyn M Sue3,19, Shanti Balasubramaniam10,14,15, John Christodoulou8,9,5,6,7,14. 1. Genetic Metabolic Disorders Research Unit, The Children's Hospital at Westmead, Sydney, Australia. lisa.riley@health.nsw.gov.au. 2. Discipline of Child & Adolescent Health, University of Sydney, Sydney, NSW, Australia. lisa.riley@health.nsw.gov.au. 3. Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia. 4. Children's Cancer Institute & School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia. 5. Murdoch Children's Research Institute, Melbourne, Australia. 6. Victorian Clinical Genetics Services, Melbourne, VIC, Australia. 7. Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia. 8. Genetic Metabolic Disorders Research Unit, The Children's Hospital at Westmead, Sydney, Australia. 9. Discipline of Child & Adolescent Health, University of Sydney, Sydney, NSW, Australia. 10. Genetic Metabolic Disorders Service, The Children's Hospital at Westmead, Sydney, NSW, Australia. 11. Department of Metabolic Medicine, Queensland Children's Hospital, Brisbane, QLD, Australia. 12. School of Clinical Medicine, University of Queensland, Brisbane, QLD, Australia. 13. School of Medicine, Griffith University, Gold Coast, QLD, Australia. 14. Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, Sydney, NSW, Australia. 15. Metabolic Unit, Department of Rheumatology and Metabolic Medicine, Perth Children's Hospital, Perth, Australia. 16. Department of Neurology, Princess Margaret Hospital for Children/Perth Children's Hospital, Perth, WA, Australia. 17. School of Paediatrics and Child Health, University of Western Australia, Perth, WA, Australia. 18. Department of Clinical Genetics, Sydney Children's Hospital Randwick, Sydney, NSW, Australia. 19. Department of Neurogenetics, Kolling Institute of Medical Research, University of Sydney and Royal North Shore Hospital, Sydney, NSW, Australia.
Abstract
PURPOSE: The utility of genome sequencing (GS) in the diagnosis of suspected pediatric mitochondrial disease (MD) was investigated. METHODS: An Australian cohort of 40 pediatric patients with clinical features suggestive of MD were classified using the modified Nijmegen mitochondrial disease severity scoring into definite (17), probable (17), and possible (6) MD groups. Trio GS was performed using DNA extracted from patient and parent blood. Data were analyzed for single-nucleotide variants, indels, mitochondrial DNA variants, and structural variants. RESULTS: A definitive MD gene molecular diagnosis was made in 15 cases and a likely MD molecular diagnosis in a further five cases. Causative mitochondrial DNA (mtDNA) variants were identified in four of these cases. Three potential novel MD genes were identified. In seven cases, causative variants were identified in known disease genes with no previous evidence of causing a primary MD. Diagnostic rates were higher in patients classified as having definite MD. CONCLUSION: GS efficiently identifies variants in MD genes of both nuclear and mitochondrial origin. A likely molecular diagnosis was identified in 67% of cases and a definitive molecular diagnosis achieved in 55% of cases. This study highlights the value of GS for a phenotypically and genetically heterogeneous disorder like MD.
PURPOSE: The utility of genome sequencing (GS) in the diagnosis of suspected pediatric mitochondrial disease (MD) was investigated. METHODS: An Australian cohort of 40 pediatric patients with clinical features suggestive of MD were classified using the modified Nijmegen mitochondrial disease severity scoring into definite (17), probable (17), and possible (6) MD groups. Trio GS was performed using DNA extracted from patient and parent blood. Data were analyzed for single-nucleotide variants, indels, mitochondrial DNA variants, and structural variants. RESULTS: A definitive MD gene molecular diagnosis was made in 15 cases and a likely MD molecular diagnosis in a further five cases. Causative mitochondrial DNA (mtDNA) variants were identified in four of these cases. Three potential novel MD genes were identified. In seven cases, causative variants were identified in known disease genes with no previous evidence of causing a primary MD. Diagnostic rates were higher in patients classified as having definite MD. CONCLUSION: GS efficiently identifies variants in MD genes of both nuclear and mitochondrial origin. A likely molecular diagnosis was identified in 67% of cases and a definitive molecular diagnosis achieved in 55% of cases. This study highlights the value of GS for a phenotypically and genetically heterogeneous disorder like MD.
Authors: Eva M M Hoytema van Konijnenburg; Saskia B Wortmann; Marina J Koelewijn; Laura A Tseng; Roderick Houben; Sylvia Stöckler-Ipsiroglu; Carlos R Ferreira; Clara D M van Karnebeek Journal: Orphanet J Rare Dis Date: 2021-04-12 Impact factor: 4.123
Authors: Rocio Rius; Alison G Compton; Naomi L Baker; AnneMarie E Welch; David Coman; Maina P Kava; Andre E Minoche; Mark J Cowley; David R Thorburn; John Christodoulou Journal: Genes (Basel) Date: 2021-04-20 Impact factor: 4.096
Authors: Katherine R Schon; Rita Horvath; Wei Wei; Claudia Calabrese; Arianna Tucci; Kristina Ibañez; Thiloka Ratnaike; Robert D S Pitceathly; Enrico Bugiardini; Rosaline Quinlivan; Michael G Hanna; Emma Clement; Emma Ashton; John A Sayer; Paul Brennan; Dragana Josifova; Louise Izatt; Carl Fratter; Victoria Nesbitt; Timothy Barrett; Dominic J McMullen; Audrey Smith; Charulata Deshpande; Sarah F Smithson; Richard Festenstein; Natalie Canham; Mark Caulfield; Henry Houlden; Shamima Rahman; Patrick F Chinnery Journal: BMJ Date: 2021-11-03