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

Katherine R. Schon, Rita Horvath, Wei Wei, Claudia Calabrese, Arianna Tucci, Kristina Ibañez, Thiloka Ratnaike, Robert D. S. Pitceathly, Enrico Bugiardini, Rosaline Quinlivan, Michael G. Hanna, Emma Clement, Emma Ashton, John A. Sayer, Paul Brennan, Dragana Josifova, Louise Izatt, Carl Fratter, Victoria Nesbitt, Timothy BarrettDominic J. McMullen, Audrey Smith, Charulata Deshpande, Sarah F. Smithson, Richard Festenstein, Natalie Canham, Mark Caulfield, Henry Houlden, Shamima Rahman, Patrick F. Chinnery (Lead / Corresponding author),

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)
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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.

Original languageEnglish
Article numbere066288
Number of pages16
JournalBMJ
Volume375
DOIs
Publication statusPublished - 4 Nov 2021

ASJC Scopus subject areas

  • General Medicine

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