mtSEEK® Mitochondrial DNA Sequencing Resource Guide

What is mtDNA sequencing?

Sequencing of the mtDNA:

mtDNA sequencing detects sequence variants present in the mitochondrial DNA. This genetic material is located within the mitochondria, and is separate from the nuclear genes, which are located on the chromosomes in the cell’s nucleus. While each cell typically has only two copies of each nuclear gene (one on each chromosome), mtDNA is present in approximately fifty to thousands of copies in a cell. mtDNA is also inherited from the mother only (maternally inherited), whereas nuclear genes are inherited from both parents. Variants in the mtDNA can result in decreased energy production within the cell, which will manifest as mitochondrial disease.


Heteroplasmic variants occur when not all copies of the mtDNA contain the variant. The percentage of heteroplasmy is the percentage of the mtDNA in which the variant was identified vs. the reference sequence. Heteroplasmy levels often vary among family members, with individuals with higher heteroplasmy levels typically presenting as more severely affected. Heteroplasmy levels also often vary among tissues of an individual, and this can affect the clinical presentation of a heteroplasmic pathogenic variant. However, the proportion of heteroplasmy in rapidly dividing tissues such as leukocytes (the source of most DNA in blood and saliva) does not necessarily reflect the proportion in slowly dividing tissues, such as nerve and muscle. Heteroplasmic variants can also arise in a patient as a de novo change (a new change in that patient’s DNA that was not inherited from the mother). Testing of additional maternal relatives is sometimes indicated to determine if the variant is inherited and the extent of heteroplasmy levels of other family members.


This term reflects the absence of detectable heteroplasmy, meaning that 99-100% of the mtDNA molecules in the sample have the same nucleotide in this position. Homoplasmic variants listed in the interpretation section of the report are highly likely to be present in other maternal relatives, as mitochondria are maternally inherited. In rare cases, a homoplasmic variant can be a de novo mutation (a new change in that patient’s DNA that was not inherited from the mother) or present in the heteroplasmic form in the mother. Homoplasmic variants are usually benign, but they can cause or predispose towards disease. If a homoplasmic variant is associated with disease, other family members with the same mtDNA sequence (e.g. mother, siblings, etc.) are predicted to have varying neurological and/or "functional" disease manifestations. A detailed family history looking for these manifestations is indicated. In particular, inquire regarding disease related to the following systems: neurological (e.g. seizures, ataxia, early-onset stroke), hearing/vision (retinopathy, sensorineural hearing loss), functional/dysautonomic (e.g. migraine and other chronic pain syndromes, fatigue, gastrointestinal dysmotility, dizziness/POTS, arrhythmia), psychiatric (depression, anxiety), cognitive (intellectual disability, autistic spectrum disorders, ADHD), and muscular (weakness, ophthalmoplegia, ptosis, cardiomyopathy), in additional to a general overview of body systems (including endocrinopathies, pancytopenias), exocrine pancreatitis, liver failure, and renal tuberopathy).

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