Mitochondrial disorders

Genetic testing is clinically relevant for the following indications, including but not limited to:

• Patients with a suspected mitochondrial phenotype, such as encephalomyopathy with lactic acidosis or stroke-like episodes
• Patients scoring as probable or definite on the Nijmegen Mitochondrial Disease Criteria
• Infants and children with a suspected respiratory-chain disorder graded possible, probable or definite
• Relatives at risk through maternal or other inheritance, for predictive testing and reproductive planning

Testing is typically requested by neurologists, clinical geneticists, metabolic physicians and ophthalmologists.

Molecular genetic testing is used as the primary diagnostic step in suspected mitochondrial disease, before invasive muscle biopsy, and it supports clinical decision-making. For example, in a cohort of 319 families with suspected mitochondrial disorders, comprehensive genetic testing established a definite or probable molecular diagnosis in 31%. Given the heterogeneity of symptoms, exome analysis, including an examination of mtDNA, is appropriate when a mitochondrial disease is suspected; this is because, in 30% of cases where a mitochondrial disorder is suspected, the actual condition is not a mitochondrial disorder but rather a disease with a similar differential diagnosis (e.g., a neurological disorder unrelated to mitochondria).

• A pathogenic or likely pathogenic variant establishes the specific molecular diagnosis, identifying the causative gene or mtDNA variant and the associated condition.
• A variant of uncertain significance (VUS) cannot yet be classified as benign or pathogenic, and reanalysis can be offered later as evidence accumulates.
• In other cases, no pathogenic variant is detected in the analysed genes. A pathogenic variant cannot, however, be entirely excluded, as the causative change may lie in a gene not yet linked to the condition or in a region current methods cannot reliably capture.
• Each variant is classified according to .

An important point concerning pathogenic mtDNA variants is that the clinical relevance of a variant is dependent not only on the pathogenicity of the variant but also on the heteroplasmic state of this variant in the affected tissue. Because each cell has not only two copies of a gene as it is usually the case for nuclear genes, but many copies (~1,000) the variant can be present in a certain amount (heteroplasmy) in a cell. This heteroplasmy can be different in distinct groups of cells, e.g., tissues. For each pathogenic mtDNA variant there is a threshold of clinical relevance in each potentially affected tissue.

Testing is performed using based exome sequencing including sequencing of the mtDNA.

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