Does Whole Exome Sequencing (WES) include mitochondrial DNA (mtDNA)?

📍Key Takeaways

1. One test, both genomes. 3billion’s enhanced WES captures the mitochondrial genome alongside the nuclear exome — so you can investigate both potential sources of disease without ordering a separate mtDNA test.
2. No fork in the road at ordering. Since mitochondrial disorders often mimic other conditions, you don’t have to decide upfront which genome to target. Both are interrogated from a single sample, in one test.
3. A wider net from the first test. Capturing the mitochondrial genome within the exome improves the chance of finding a diagnostic variant that a standard exome alone might miss, though some findings may still need tissue-based validation.

Mitochondrial diseases are a group of genetic disorders that primarily affect the function of mitochondria, the energy-producing structures within cells. These disorders can arise from variants in either mitochondrial DNA or nuclear DNA. Variants in nuclear genes associated with mitochondrial function are often included in the targeted gene panels or exome sequencing tests used in clinical settings.

In general, WES focuses on sequencing the protein-coding regions of the nuclear genome, known as the exome. This means that the primary target of WES is the DNA found within the cell nucleus, which does not include the entirety of the mitochondrial genome.

If a suspected mitochondrial disease is being investigated, clinicians should consider additional testing methods, such as mitochondrial DNA sequencing or targeted panels that specifically focus on mitochondrial genes. These specialized tests can provide a more comprehensive analysis of mitochondrial DNA mutations, complementing the information obtained from exome sequencing. That said, some WES services do offer additional analysis or options that include mitochondrial DNA. This may involve specific bioinformatics pipelines, or the use of specialized sequencing panels or capture kits that target both the nuclear exome and the mitochondrial genome.

Why is 3billion’s WES different?

With 3billion’s enhanced whole exome sequencing service, the mean depth of coverage now reaches around 100X, and the mitochondrial genome is sequenced at approximately 2,000X. We have also improved coverage of the RPGR ORF15 exon, a well-known exome coverage drop-out region despite the many disease-causing variants reported within it. And we’re not done yet: the intronic regions of the GLA and RPE65 genes, along with a large number of non-coding disease-causing variant positions, are now covered as well.

What this means when you’re ordering a test

The practical advantage shows up at the moment of ordering. Because mitochondrial disorders mimic so many other conditions, clinicians often can’t tell upfront whether a patient’s symptoms trace back to the nuclear genome or the mitochondrial one. The conventional route is to run an exome first and, if it comes back negative, order a separate mtDNA test — another order, more turnaround time, and sometimes another sample. By capturing the mitochondrial genome within the same exome test, 3billion lets you interrogate both from a single sample, in one test — without having to commit to one path at the outset.

One thing worth keeping in mind: detecting an mtDNA variant isn’t always the final step. Mitochondrial variants are reported at a heteroplasmy level of 5% or higher, and variants concentrated in a specific affected tissue may still require tissue-based validation to interpret. The benefit lies in casting a wider net from the very first test — not in removing every possible follow-up.

If you’re specifically interested in including mitochondrial DNA detection in a WES service, ask our team about the details!