For patients and families

What is mitochondrial DNA?

Mitochondria help supply cells with energy. They contain a small genome of their own, called mitochondrial DNA (mtDNA), which children inherit from their mother.

Cells typically contain hundreds or thousands of mtDNA copies. A pathogenic variant is a change that can cause disease. It is usually inherited from the mother, although it can arise for the first time. Often, only some mtDNA copies carry the variant. Their proportion is called the heteroplasmy level and is expressed as a percentage.

In the same woman, heteroplasmy levels may differ between blood, urine, muscle and individual eggs (oocytes).

PGT-mt is useful when a woman carries a pathogenic mtDNA variant in a heteroplasmic state: some copies carry the variant and others do not. If every copy carries it (homoplasmy), testing cannot identify an embryo with a lower proportion. If the disease is caused by a variant in a nuclear gene, a different test, PGT-M, is needed. Men do not pass mtDNA variants to their children.

How PGT-mt works

During in vitro fertilisation (IVF), cells are sampled on day 3 or days 5–6. Usually, this means one blastomere (an early embryo cell) on day 3, or several trophectoderm cells on days 5–6. Trophectoderm is the outer layer that contributes to the placenta. The laboratory measures the proportion of mtDNA carrying the variant in this sample.

Embryos from the same woman may have different heteroplasmy levels. Testing helps identify the embryo with the lowest level, provided it falls below a cut-off agreed beforehand with the clinical geneticist for the specific variant. If all embryos exceed that cut-off, transfer is generally not recommended.

The outcome cannot be predicted precisely before a cycle begins. The number of embryos with low heteroplasmy varies between patients and treatment cycles; some cycles yield none.

Why is a percentage not a diagnosis?

PGT-mt compares embryo heteroplasmy levels against an agreed cut-off. It cannot determine whether a future child will develop mitochondrial disease.

The test measures the proportion of mtDNA carrying the variant in one or a few cells at a single time point. The child’s health depends on how that variant is distributed across tissues and organs later in development.

There is no universal “safe” heteroplasmy percentage. Published reference values come from different types of evidence: 18% is an estimate based on muscle measurements in adult carriers, whereas 30% is an embryo-selection criterion used by one clinical programme. Thresholds differ between mtDNA variants, and no value guarantees a healthy child. Chapter 6 of the fundamentals course explains these distinctions.

PGT-mt and chromosome testing (PGT-A)

Chromosome number also affects the chances of pregnancy and the child’s health. PGT-mt can be combined on the same sample with preimplantation genetic testing for aneuploidy (PGT-A), which assesses chromosome number. The doctor and family decide whether to use it, taking maternal age into account.

As maternal age increases, the proportion of embryos with the expected chromosome number falls. This often limits embryo selection more than mtDNA heteroplasmy does.

The risk is reduced, not removed

Published data indicate that PGT-mt reduces the risk of transmitting mitochondrial disease, but does not eliminate it.

Discuss prenatal diagnosis with your doctor before any PGT-mt transfer, including when the variant was not detected in the biopsy sample. “Not detected” means that the test did not detect the variant within its analytical limits; it does not establish “0%”.

There may be no embryo in which the variant is entirely absent. Doctors therefore plan follow-up during pregnancy and after birth in advance.

Your doctor can also help prepare an individual plan for monitoring your child’s health and development after birth.

What other options are there?

PGT-mt is one of several reproductive options:

• Prenatal diagnosis — testing during pregnancy, using chorionic villi or amniotic fluid. For a homoplasmic variant, measuring its proportion alone cannot predict whether the child will be affected.
• Donor eggs — using oocytes from a healthy donor. The child will inherit nuclear DNA and mtDNA from the egg donor rather than the intended mother.
• Mitochondrial donation — transferring the patient’s nuclear material into a donor oocyte or zygote containing mtDNA without the pathogenic variant. Availability depends on national legislation. A small amount of maternal mtDNA may be carried over with the nuclear material, so the risk is reduced rather than eliminated.

How do you choose?

There is no single option that suits everyone. The choice depends on the mtDNA variant, family history, available techniques and access to treatment. Decisions are individual and should be made through an open discussion with your fertility specialist and clinical geneticist.

Terms explained

mtDNA

The small genome found in mitochondria.

Pathogenic variant

A DNA change that can cause disease.

Heteroplasmy

The presence of different versions of mtDNA in the same cell or sample.

Homoplasmy

The same variant in all mtDNA copies.

Heteroplasmy level

The proportion of mtDNA copies carrying the variant being tested, expressed as a percentage.

Biopsy sample

A small sample of cells removed for testing.

Blastomere

A cell of an early embryo.

Trophectoderm

The outer cell layer of a blastocyst, which contributes to the placenta.

Oocyte and zygote

An oocyte is an egg cell; a zygote is the cell formed after fertilisation.

Nuclear material

DNA in the cell nucleus, distinct from mtDNA.