The diagnostic utility of genome sequencing in a pediatric cohort with suspected mitochondrial disease

Lisa G. Riley, Mark J. Cowley, Velimir Gayevskiy, Andre E. Minoche, Clare Puttick, David R. Thorburn, Rocio Rius, Alison G. Compton, Minal J. Menezes, Kaustuv Bhattacharya, David Coman, Carolyn Ellaway, Ian E. Alexander, Louisa Adams, Maina Kava, Jacqui Robinson, Carolyn M. Sue, Shanti Balasubramaniam, John Christodoulou

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1254-1261
Number of pages8
JournalGenetics in Medicine
Issue number7
Publication statusPublished - 1 Jul 2020


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