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

Lookup NU author(s): Professor Rita HorvathORCiD, Dr Wei Wei, Dr Robert Pitceathly, Professor Michael Hanna, Professor John SayerORCiD, Dr Paul Brennan, Dr Victoria Nesbitt, Professor Patrick Chinnery



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 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.

Publication metadata

Author(s): Schon KR, Horvath R, Wei W, Calabrese C, Tucci A, Ibanez K, Ratnaike T, Pitceathly RDS, Bugiardini E, Quinlivan R, Hanna MG, Clement E, Ashton E, Sayer JA, Brennan P, Josifova D, Izatt L, Fratter C, Nesbitt V, Barrett T, McMullen DJ, Smith A, Deshpande C, Smithson SF, Festenstein R, Canham N, Caulfield M, Houlden H, Rahman S, Chinnery PF, Ambrose JC, Arumugam P, Bevers R, Bleda M, Boardman-Pretty F, Boustred CR, Brittain H, Caulfield MJ, Chan GC, Elgar G, Fowler T, Giess A, Hamblin A, Henderson S, Hubbard TJP, Jackson R, Jones LJ, Kasperaviciute D, Kayikci M, Kousathanas A, Lahnstein L, Leigh SEA, Leong IUS, Lopez FJ, Maleady-Crowe F, McEntegart M, Minneci F, Moutsianas L, Mueller M, Murugaesu N, Need AC, O'Donovan P, Odhams CA, Patch C, Pereira MB, Perez-Gil D, Pullinger J, Rahim T, Rendon A, Rogers T, Savage K, Sawant K, Scott RH, Siddiq A, Sieghart A, Smith SC, Sosinsky A, Stuckey A, Tanguy M, Taylor Tavares AL, Thomas ERA, Thompson SR, Tucci A, Welland MJ, Williams E, Witkowska KA, Wood SM

Publication type: Article

Publication status: Published

Journal: The BMJ

Year: 2021

Volume: 375

Online publication date: 04/11/2021

Acceptance date: 11/10/2021

Date deposited: 25/10/2023

ISSN (print): 0959-8146

ISSN (electronic): 1756-1833

Publisher: BMJ Publishing Group


DOI: 10.1136/bmj-2021-066288


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Funder referenceFunder name
100 000 Genomes Project
109915/Z/15/ZWellcome Trust
Addenbrooke’s Charitable Trust
Alzheimer’s Society project grant AS-PG-18b-022
Evelyn Trust
Lily Foundation
Medical Research Council (MRC)
Imperial NIHR BRC Imperial College Healthcare Trust
MR/N027302/1Medical Research Council (MRC)
MR/S005021/1Medical Research Council (MRC)
MRC clinician scientist fellowship MR/S002065/1
MR/N025431/1Medical Research Council (MRC)
MRC Mitochondrial Biology UnitMC_UU_00015/9
MRC research grant MR/S035699/1
National Institute for Health Research (NIHR)
NIHR Biomedical Research Centre
NHS England
the European Research Council
the Leverhulme Trust RPG-2018-408
The Wellcome Trust, Cancer Research UK
UK NHS Highly Specialised Commissioners
Wellcome Trust principal research fellowship 212219/Z/18/Z