Mitochondrial Diseases: A Diagnostic Revolution

Schon, Katherine; Ratnaike, Thiloka; Ameele, Jelle van den; Horváth, Rita; Chinnery, Patrick F.

doi:10.1016/j.tig.2020.06.009

Cited by 84 publications

(70 citation statements)

References 115 publications

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“…This information is crucial for the provision of genetic counselling and the accurate estimation of recurrence risk for future pregnancies. Together, these studies validate the importance of an unbiased genetics‐first approach for these families in their time of clinical need [29,30].…”

Section: Mitochondrial Genomicsmentioning

confidence: 70%

The genetics of mitochondrial disease: dissecting mitochondrial pathology using multi‐omic pipelines

Alston

Stenton

Hudson

et al. 2021

The Journal of Pathology

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Mitochondria play essential roles in numerous metabolic pathways including the synthesis of adenosine triphosphate through oxidative phosphorylation. Clinically, mitochondrial diseases occur when there is mitochondrial dysfunction – manifesting at any age and affecting any organ system; tissues with high energy requirements, such as muscle and the brain, are often affected. The clinical heterogeneity is parallel to the degree of genetic heterogeneity associated with mitochondrial dysfunction. Around 10% of human genes are predicted to have a mitochondrial function, and defects in over 300 genes are reported to cause mitochondrial disease. Some involve the mitochondrial genome (mtDNA), but the vast majority occur within the nuclear genome. Except for a few specific genetic defects, there remains no cure for mitochondrial diseases, which means that a genetic diagnosis is imperative for genetic counselling and the provision of reproductive options for at‐risk families. Next‐generation sequencing strategies, particularly exome and whole‐genome sequencing, have revolutionised mitochondrial diagnostics such that the traditional muscle biopsy has largely been replaced with a minimally‐invasive blood sample for an unbiased approach to genetic diagnosis. Where these genomic approaches have not identified a causative defect, or where there is insufficient support for pathogenicity, additional functional investigations are required. The application of supplementary ‘omics’ technologies, including transcriptomics, proteomics, and metabolomics, has the potential to greatly improve diagnostic strategies. This review aims to demonstrate that whilst a molecular diagnosis can be achieved for many cases through next‐generation sequencing of blood DNA, the use of patient tissues and an integrated, multidisciplinary multi‐omics approach is pivotal for the diagnosis of more challenging cases. Moreover, the analysis of clinically relevant tissues from affected individuals remains crucial for understanding the molecular mechanisms underlying mitochondrial pathology. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

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Section: Mitochondrial Genomicsmentioning

confidence: 70%

The genetics of mitochondrial disease: dissecting mitochondrial pathology using multi‐omic pipelines

Alston

Stenton

Hudson

et al. 2021

The Journal of Pathology

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“…The collaboration of clinicians and researchers facilitates an exchange of data worldwide, accelerates gene discoveries, and improves our understanding of genotypephenotype correlations. This provides the opportunity to coordinate sufficiently powered clinical trials (Schon et al, 2020). The emergence of national mitochondrial patient registers over the last few years (e.g., mitoNET, MITOCON, NAMDC) has not only enabled large-scale NGS studies to be conducted to further clarify genotype-phenotype correlation (Altmann et al, 2016).…”

Section: Future Perspectivesmentioning

confidence: 99%

The Dimensions of Primary Mitochondrial Disorders

Schlieben

Prokisch

2020

Front. Cell Dev. Biol.

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The concept of a mitochondrial disorder was initially described in 1962, in a patient with altered energy metabolism. Over time, mitochondrial energy metabolism has been discovered to be influenced by a vast number of proteins with a multitude of functional roles. Amongst these, defective oxidative phosphorylation arose as the hallmark of mitochondrial disorders. In the premolecular era, the diagnosis of mitochondrial disease was dependent on biochemical criteria, with inherent limitations such as tissue availability and specificity, preanalytical and analytical artifacts, and secondary effects. With the identification of the first mitochondrial disease-causing mutations, the genetic complexity of mitochondrial disorders began to unravel. Mitochondrial dysfunctions can be caused by pathogenic variants in genes encoded by the mitochondrial DNA or the nuclear DNA, and can display heterogenous phenotypic manifestations. The application of next generation sequencing methodologies in diagnostics is proving to be pivotal in finding the molecular diagnosis and has been instrumental in the discovery of a growing list of novel mitochondrial disease genes. In the molecular era, the diagnosis of a mitochondrial disorder, suspected on clinical grounds, is increasingly based on variant detection and associated statistical support, while invasive biopsies and biochemical assays are conducted to an ever-decreasing extent. At present, there is no uniform biochemical or molecular definition for the designation of a disease as a “mitochondrial disorder”. Such designation is currently dependent on the criteria applied, which may encompass clinical, genetic, biochemical, functional, and/or mitochondrial protein localization criteria. Given this variation, numerous gene lists emerge, ranging from 270 to over 400 proposed mitochondrial disease genes. Herein we provide an overview of the mitochondrial disease associated genes and their accompanying challenges.

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“…However, most mitochondrial proteins are encoded by nuclear DNA, and after transcription, they are imported into the mitochondrial compartment. 1 In contrast to nuclear DNA, which is inherited from both parents, mDNA shows strict maternal inheritance. Mutations in nuclear mitochondrial genes may be inherited as an autosomal recessive, X-linked recessive, or autosomal dominant trait.…”

mentioning

confidence: 99%

“…This marked genetic heterogeneity may complicate diagnosis and genetic counselling. 1 Mitochondrial disorders affect approximately 1 in 5000 of the population. 2 Although tissues with high energetic demands such as the brain and the eye are more likely to be affected, patients can demonstrate highly variable clinical manifestations even within the same family segregating the same disease-causing variant.…”

mentioning

confidence: 99%

“…The ability to sequence the complete human genome, including mDNA, will lead to a diagnostic revolution in our approach to patients with suspected mitochondrial disorders. 1 Even more tantalizing is the possibility that detailed analysis of the whole genome sequence may lead to the identification of modifier gene variants that contribute to the variable tissue specificity and disease severity seen in this group of disorders.…”

mentioning

confidence: 99%

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