Preimplantation genetic testing

Preimplantation genetic testing (PGT) is a type of IVF procedure used to identify disease-causing genetic variants and avoid the implantation of affected embryos. Subcategories of PGT include PGT for monogenic disorders (PGT-M) and PGT for structural rearrangements such as translocations (PGT-SR). PGT-M was previously known as preimplantation genetic diagnosis (PGD).

Other types of PGT include PGT for aneuploidy (PGT-A), which is a type of PGT used in cases of recurrent miscarriages of unknown aetiology, and PGT for polygenic risk (PGT-P). PGT-P does not currently have a legal license for use in the UK due to the lack of scientific consensus about it.

If there is a chance that a pregnancy may be affected by a familial genetic condition, some families wish to take steps to ensure that it will not be affected. Most couples requesting PGT do so to avoid the possibility of terminating a pregnancy following non-invasive prenatal diagnosis or if they already require IVF due to subfertility.

An embryo is created using IVF, from which a few cells are tested before it is transferred to the womb. Most embryo testing takes place at blastocyst stage (day five to day seven). Only embryos without the disease-causing genetic variant(s) are transferred, preventing the child from developing the condition that has been tested for. Alternatively, couples can choose to have their embryos frozen for future use.

Time from first PGT appointment to the start of treatment is currently estimated at between eight and 18 months. Any application for a Human Fertilisation & Embryology Authority (HFEA) license (see below) will add to this estimate.

The HFEA regulates all assisted reproductive techniques, including PGT.

Once a specific disease-causing gene variant is known, it is technically possible to use PGT-M to test for that variant. However, in order to comply with legal criteria, genetic conditions are required to have a specific HFEA licence. The HFEA considers various factors in each condition, including the likelihood of the condition being inherited and the seriousness of the symptoms. There is a list of approved PGT-M conditions available online.

If a specific condition is not already on the approved list, a licensed PGT-M clinic can, on the patient’s behalf, apply to have the condition considered for approval for licencing. A list of PGT-M clinics is available online. License approvals are typically made within two to three months.

To receive up to three NHS-funded cycles of intracytoplasmic sperm injection or IVF in conjunction with PGT, couples must meet the following criteria:

• the chance of conceiving a pregnancy affected by a serious genetic condition must be 10% or more;
• the couple must have been referred to the PGT provider by an NHS clinical genetics service;
• the couple must have received genetic counselling from a clinical geneticist or a registered genetic counsellor;
• the female partner must be under 40 years of age at the time of treatment;
• the female partner must have a BMI of more than 19 and less than 30;
• both partners must be non-smokers, including e-cigarettes;
• there must be no living unaffected child from the current relationship;
• the couple must have been together for at least a year, and currently living at the same address;
• the HFEA must have licensed the indication for PGT; and
• the couple must not be seeking PGT primarily because they are infertile and must not, for any other reason, be unable to have children on their own.

Self-funding of PGT is also an option for some families.

Approximately one third of women will have a successful pregnancy after each cycle of IVF with PGT, which is comparable to those undertaking assisted reproduction for reasons of infertility. Approximately 50% of couples have a successful embryo transfer. Up-to-date success rates are available online.

While IVF procedures are generally safe, they are not without potential side effects.

There is a small chance of the results of PGT being inaccurate. This may occur due to mosaicism within the blastocyst, or allelic dropout, resulting in amplification and interpretation of only one of the parent alleles being tested.

• PGT is a type of IVF procedure that can diagnose affected embryos prior to implantation.
• In order for PGT-M or PGT-SR to be undertaken, the disease-causing variant must be known.
• Strict criteria apply, both to conditions that are licensed for PGT and to patients who wish to undergo an IVF procedure under the NHS.
• Couples must be adequately counselled regarding the success of PGT, risk factors and the timeline to treatment.

For clinicians

• Guy’s and St Thomas’ NHS Foundation Trust: Pre-implantation genetic testing (PGT-M/SR)
• Gov.uk Guidance: Counselling and referral for prenatal diagnosis (PND)
• Human Fertilisation & Embryology Authority: Approved PGT-M and PTT conditions
• Human Fertilisation & Embryology Authority: Pre-implantation genetic testing for monogenic disorders (PGT-M) and Pre-implantation genetic testing for chromosomal structural rearrangements (PGT-SR)
• NHS England: National Genomic Test Directory

References:

• Greco E, Litwicka K, Minasi MG, and others. ‘Preimplantation Genetic Testing: Where We Are Today’. International Journal of Molecular Sciences 2020: volume 21, issue 12, page 4,381. DOI: 10.3390/ijms21124381

For patients

• Genetic Alliance: Preimplantation genetic diagnosis and the HFEA’s role
• Genetic Alliance: Preimplantation genetic diagnosis: Benefits and risk
• Guy’s and St Thomas’ NHS Foundation Trust: Pre-implantation genetic testing (PGT-M/SR)
• Manchester University NHS Foundation Trust: Pre-implantation genetic testing (PGT) (PDF, four pages)