Journal
GENETICS IN MEDICINE
Volume 22, Issue 7, Pages 1254-1261Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/s41436-020-0793-6
Keywords
genome sequencing; mitochondrial disease; pediatric; diagnosis; respiratory chain
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Funding
- New South Wales Office of Health and Medical Research Council Sydney Genomics Collaborative grant
- National Health and Medical Research Council (NHMRC) [1026891]
- NHMRC [1102896]
- NSW Health Early-Mid Career Fellowship
- Victorian Government's Operational Infrastructure Support Program
- Crane family
- Perkins family
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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.
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