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Genetic testing for mitochondrial disease: the United Kingdom best practice guidelines

Lookup NU author(s): Eleni Mavraki, Dr Charlotte Alston, Charlotte Knowles, Jack Baines, Professor Robert Taylor



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


© 2022, The Author(s). Primary mitochondrial disease describes a diverse group of neuro-metabolic disorders characterised by impaired oxidative phosphorylation. Diagnosis is challenging; >350 genes, both nuclear and mitochondrial DNA (mtDNA) encoded, are known to cause mitochondrial disease, leading to all possible inheritance patterns and further complicated by heteroplasmy of the multicopy mitochondrial genome. Technological advances, particularly next-generation sequencing, have driven a shift in diagnostic practice from ‘biopsy first’ to genome-wide analyses of blood and/or urine DNA. This has led to the need for a reference framework for laboratories involved in mitochondrial genetic testing to facilitate a consistent high-quality service. In the United Kingdom, consensus guidelines have been prepared by a working group of Clinical Scientists from the NHS Highly Specialised Service followed by national laboratory consultation. These guidelines summarise current recommended technologies and methodologies for the analysis of mtDNA and nuclear-encoded genes in patients with suspected mitochondrial disease. Genetic testing strategies for diagnosis, family testing and reproductive options including prenatal diagnosis are outlined. Importantly, recommendations for the minimum levels of mtDNA testing for the most common referral reasons are included, as well as guidance on appropriate referrals and information on the minimal appropriate gene content of panels when analysing nuclear mitochondrial genes. Finally, variant interpretation and recommendations for reporting of results are discussed, focussing particularly on the challenges of interpreting and reporting mtDNA variants.

Publication metadata

Author(s): Mavraki E, Labrum R, Sergeant K, Alston CL, Woodward C, Smith C, Knowles CVY, Patel Y, Hodsdon P, Baines JP, Blakely EL, Polke J, Taylor RW, Fratter C

Publication type: Article

Publication status: Published

Journal: European Journal of Human Genetics

Year: 2023

Volume: 31

Pages: 148-163

Print publication date: 01/02/2023

Online publication date: 13/12/2022

Acceptance date: 16/11/2022

Date deposited: 05/01/2023

ISSN (print): 1018-4813

ISSN (electronic): 1476-5438

Publisher: Springer Nature


DOI: 10.1038/s41431-022-01249-w


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Funder referenceFunder name
203105/Z/16/ZWellcome Trust
Lily Foundation
MR/S005021/1Medical Research Council (MRC)
NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust
Pathological Society