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

Abstract

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.

Investigation of FGF21 mRNA levels and relative mitochondrial DNA copy number levels and their relation in nonalcoholic fatty liver disease: a case-control study

“…Thus, measuring relative mtDNA-CN as determining factor for mitochondrial damage and activity rate can be helpful for identifying the stage and prognosis of the disease ( Cao et al, 2020 ; Filograna et al, 2021 ). On the other hand, in some stages of different mitochondrial disorders mtDNA-CN can be within the normal range and its changes should be interpreted along with clinical, histological, and other laboratory findings ( Mavraki et al, 2023 ). However, despite its flows, mtDNA-CN is widely accepted among researchers as a useful method to assess mitochondrial function ( Castellani et al, 2020 ; Zhang et al, 2022 ).…”

Electrolyte Disorders in Mitochondrial Cytopathies: A Systematic Review

“…119,120 Therefore, the secondary genetic testing strategy should explicitly aim to capture mtDNA/nDNA variations that could cause a mitochondrial disease. 121 A special instance in which first-tier testing for a mitochondrial disease should be considered is in patients with a maternal inheritance pattern or multiorgan involvement. Finally, we propose to incorporate the mtDNA genes MT-TI and MT-TF in the primary genetic testing strategy because patients with variants in these genes usually present without any other organ involvement.…”

New Mitochondrial Disease Identified In Monozygotic Twin Boys

“…Clinically heterogeneous, mitochondrial disorders can affect isolated or multiple organ systems, may manifest at any age, and are typically associated with significant morbidity and mortality (Mavraki et al, 2022). Estimated prevalence is approximately 12.5 per 100,000 among adults and 4.7 per 100,000 in children, although the frequency of pathogenic mtDNA variants in the general population is estimated to be higher, with as many as 1 in 250 healthy individuals carrying a pathogenic mtDNA variant at low levels.…”