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

Lisa G Riley^{1

2}, Mark J Cowley^{3

4}, Velimir Gayevskiy³, Andre E Minoche³, Clare Puttick³, David R Thorburn^{5

6

7}, Rocio Rius⁵, Alison G Compton⁵, Minal J Menezes^{8

9}, Kaustuv Bhattacharya^{9

10}, David Coman^{11

12

13}, Carolyn Ellaway^{9

10

14}, Ian E Alexander^{9

10}, Louisa Adams^{9

10

14}, Maina Kava^{15

16

17}, Jacqui Robinson¹⁸, Carolyn M Sue^{3

19}, Shanti Balasubramaniam^{10

14

15}, John Christodoulou^{8

9

5

6

7

14}

Affiliations

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.

PMID: 32313153
DOI: 10.1038/s41436-020-0793-6

Free article

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

Lisa G Riley et al. Genet Med. 2020 Jul.

Free article

. 2020 Jul;22(7):1254-1261.

doi: 10.1038/s41436-020-0793-6. Epub 2020 Apr 21.

Authors

Affiliations

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.

PMID: 32313153
DOI: 10.1038/s41436-020-0793-6

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.

Keywords: diagnosis; genome sequencing; mitochondrial disease; pediatric; respiratory chain.

PubMed Disclaimer

References

1. Gorman S, Chinnery P, DiMauro S, et al. Mitochondrial diseases. Nat Rev Dis Primers. 2016;2:16080. - DOI
1. Frazier A, Thorburn D, Compton A. Mitochondrial energy generation disorders: genes, mechanisms and clues to pathology. J Biol Chem. 2017;294:5386–5395. - DOI
1. Stenton S, Prokisch H. Advancing genomic approached to the molecular diagnosis of mitochondrial disease. Essays Biochem. 2018;62:399–408. - DOI
1. Rahman J, Rahman S. Mitochondrial medicine in the omics era. Lancet. 2018;391:2560–2574. - DOI
1. Vafai S, Mootha V. Mitochondrial disorders as windows into an ancient organelle. Nature. 2012;491:374–383. - DOI

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions

LinkOut - more resources

Full Text Sources
- Elsevier Science
Medical
- MedlinePlus Health Information
Molecular Biology Databases
- The Weizmann Institute of Science GeneCards and MalaCards databases

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases