Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study
Authors
Horvath, Rita
Wei, Wei
Calabrese, Claudia
Tucci, Arianna
Ibañez, Kristina
Ratnaike, Thiloka
Pitceathly, Robert D S
Bugiardini, Enrico
Quinlivan, Rosaline
Hanna, Michael G
Clement, Emma
Ashton, Emma
Sayer, John A
Brennan, Paul
Josifova, Dragana
Izatt, Louise
Fratter, Carl
Nesbitt, Victoria
Barrett, Timothy
McMullen, Dominic J
Smith, Audrey
Deshpande, Charulata
Smithson, Sarah F
Festenstein, Richard
Canham, Natalie
Caulfield, Mark
Genomics England Research Consortium
Ambrose, John C
Arumugam, Prabhu
Bevers, Roel
Bleda, Marta
Boardman-Pretty, Freya
Boustred, Christopher R
Brittain, Helen
Caulfield, Mark J
Chan, Georgia C
Elgar, Greg
Fowler, Tom
Giess, Adam
Hamblin, Angela
Henderson, Shirley
Hubbard, Tim J P
Jackson, Rob
Jones, Louise J
Kasperaviciute, Dalia
Kayikci, Melis
Kousathanas, Athanasios
Lahnstein, Lea
Leigh, Sarah E A
Leong, Ivonne U S
Lopez, Javier F
Maleady-Crowe, Fiona
McEntegart, Meriel
Minneci, Federico
Moutsianas, Loukas
Mueller, Michael
Murugaesu, Nirupa
Need, Anna C
O’Donovan, Peter
Odhams, Chris A
Patch, Christine
Buonerimo Pereira, Mariana
Perez-Gil, Daniel
Pullinger, John
Rahim, Tahrima
Rendon, Augusto
Rogers, Tim
Savage, Kevin
Sawant, Kushmita
Scott, Richard H
Siddiq, Afshan
Sieghart, Alexander
Smith, Samuel C
Sosinsky, Alona
Stuckey, Alexander
Tanguy, Mélanie
Taylor Tavares, Ana Lisa
Thomas, Ellen R A
Thompson, Simon R
Welland, Matthew J
Williams, Eleanor
Witkowska, Katarzyna
Wood, Suzanne M
Publication Date
2021-11-03Journal Title
BMJ
Publisher
British Medical Journal Publishing Group
Volume
375
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Schon, K. R., Horvath, R., Wei, W., Calabrese, C., Tucci, A., Ibañez, K., Ratnaike, T., et al. (2021). Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study. BMJ, 375 https://doi.org/10.1136/bmj-2021-066288
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
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.
Keywords
Research
Identifiers
bmj-2021-066288.r1, schk066288, 34732400
External DOI: https://doi.org/10.1136/bmj-2021-066288
This record's URL: https://www.repository.cam.ac.uk/handle/1810/330330
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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