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Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study

Published version
Peer-reviewed

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Authors

Horvath, Rita 
Wei, Wei 
Calabrese, Claudia 
Tucci, Arianna 

Abstract

Abstract: Objective: To determine whether whole genome sequencing can be used to define the molecular basis of suspected mitochondrial disease. Design: Cohort study. Setting: National Health Service, England, including secondary and tertiary care. Participants: 345 patients with suspected mitochondrial disorders recruited to the 100 000 Genomes Project in England between 2015 and 2018. Intervention: Short read whole genome sequencing was performed. Nuclear variants were prioritised on the basis of gene panels chosen according to phenotypes, ClinVar pathogenic/likely pathogenic variants, and the top 10 prioritised variants from Exomiser. Mitochondrial DNA variants were called using an in-house pipeline and compared with a list of pathogenic variants. Copy number variants and short tandem repeats for 13 neurological disorders were also analysed. American College of Medical Genetics guidelines were followed for classification of variants. Main outcome measure: Definite or probable genetic diagnosis. Results: A definite or probable genetic diagnosis was identified in 98/319 (31%) families, with an additional 6 (2%) possible diagnoses. Fourteen of the diagnoses (4% of the 319 families) explained only part of the clinical features. A total of 95 different genes were implicated. Of 104 families given a diagnosis, 39 (38%) had a mitochondrial diagnosis and 65 (63%) had a non-mitochondrial diagnosis. Conclusion: Whole genome sequencing is a useful diagnostic test in patients with suspected mitochondrial disorders, yielding a diagnosis in a further 31% after exclusion of common causes. Most diagnoses were non-mitochondrial disorders and included developmental disorders with intellectual disability, epileptic encephalopathies, other metabolic disorders, cardiomyopathies, and leukodystrophies. These would have been missed if a targeted approach was taken, and some have specific treatments.

Description

Funder: University of Cambridge; FundRef: http://dx.doi.org/10.13039/501100000735


Funder: Alzheimer's Society; FundRef: http://dx.doi.org/10.13039/501100000320


Funder: Leverhulme Trust; FundRef: http://dx.doi.org/10.13039/501100000275


Funder: National Institute for Health Research; FundRef: http://dx.doi.org/10.13039/501100000272


Funder: Department of Health; FundRef: http://dx.doi.org/10.13039/501100000276


Funder: Evelyn Trust; FundRef: http://dx.doi.org/10.13039/501100004282


Funder: Wellcome Trust; FundRef: http://dx.doi.org/10.13039/100004440


Funder: Medical Research Council; FundRef: http://dx.doi.org/10.13039/501100000265

Keywords

Research

Journal Title

BMJ

Conference Name

Journal ISSN

1756-1833

Volume Title

375

Publisher

British Medical Journal Publishing Group