In this live webinar, Dr Clara Colomé, Medical Deputy Director at Eugin Clinic, explained the process and role of carrier screening in IVF and egg/sperm donation.
An expanded carrier screening test is a genetic test for individuals that are at a no-risk or without a family history of recessively inherited disorders. It aims to identify healthy carriers of formal recessive or X-linked recessive inherited diseases. The objective is to assess the risk of having a child with a severe recessive disease.
All humans have 46 chromosomes, 23 come from the mother and 23 come from the father. If there is an affected copy of the mutation, but the other one, for example, coming from your father is normal, then you might be a healthy carrier of a genetic autosomal recessive disease. That means that you can be a healthy carrier for this disease, and you won’t probably find out about that unless your partner also carries the same disease. Then, when you have children together, you would have a 25% chance of having a child with a particular disease because he or she would inherit the affected chain from his father and the one from his mother.
There is another type of recessive disease which are the X-linked recessive disease. Women have 2 X-chromosomes, and men have 1 X chromosome and one Y chromosome, which means that for recessive diseases linked to the X chromosome, females can be healthy carriers of those diseases, while men cannot because they only have 1 copy of the chromosome. If it has a mutation, it will develop the disease. That means that if a healthy carrier for X-linked recessive diseases has a child, 50% of her male children will have the disease, and the other 50% will be healthy, and all baby girls will be healthy though half of them will carry the mutation as well.
There are over 10,000 diseases with a Mendelian inheritance, which has been explained above. 1,400 of them are recessive inherited diseases that are transmitted autosomally or are X-linked. Over 50% of the population could be a healthy carrier for 1 of those diseases. 3 to 4% of couples are at increased risk of having a child with 1 of those diseases. 3 to 5% of all births result in congenital malformations, which means 8 million children are born with a serious defect of partial or total genetic origin per year. 20 to 30% of all infant deaths in the world are due to genetic disease and it leads to 18% of paediatric hospitalizations.
Who should do this kind of genetic testing? Even when an egg donor is used, and they are healthy and thoroughly screened, they could still carry a genetic disease, so if we don’t look for it, we might eventually find ourselves with a child with a genetic disorder. Therefore, it is crucial to remember that recessive diseases can hide quite well. Depending on prevalence, carrier status can remain unnoticed for generations. In fact, 80% of couples with a child affected by 1 recessive disease have no relevant family history. 95% of children with hearing loss detected by universal screening that is performed and birth have both burns with normal hearing and have both parents with normal hearing.
All humans are carriers of pathogenic variants in genes associated with genetic diseases with autosomal recessive or X-linked inheritance patterns. Each one of us carries 2 to 8 severe recessive mutations and thousands of private variants of unknown effect, regardless of our ethnic origin.
When should a carrier screening test be performed?
How is this test performed? Usually, this kind of test needs a blood sample or a saliva sample. The best strategy would be to test both partners at the same time. To limit cost, both partners can be analysed just once, or one female sample could be analysed. Then the male partner sample would remain in custody for up to 3 months, and it’s only analysed if the female partner is a carrier.
Even if both partners or the donors are tested, 0% risk does not exist because every genetic technique we can apply these days has a residual risk. Even prenatal testing (PNT, NIPT) during pregnancy has residual risks even if carrier screening has a negative result. However, this test helps to reduce those risks.
If both partners carry the same genetic mutation for a recessive disorder, they could go through an IVF with PGT-M (Preimplantation Genetic Testing for Monogenic disorders) to look for this particular disease, and just transfer embryos that are not affected by the disease. There could also be an option to conceive naturally or with an assisted reproductive treatment and then to do a prenatal diagnostic during pregnancy in case the pregnancy occurs.
They could eventually go for donated gametes through IUI or an IVF with donor sperm if the male partner is the one who carries the mutation and the female wants to use her oocytes or the other way around depending on the situation. Adoption could also be considered, or refraining from having children is always a possibility that the couple has to evaluate.
The guidelines from ASRM (American Society for Reproductive Medicine), and SEF (Spanish Fertility Society) usually advise all couples to perform a karyotype, which is a very basic genetic test that shows the number and shape of chromosomes. They also advise testing for cystic fibrosis, which is a genetic disease that affects the lungs and it’s quite common in Europe. The American College of Medical Genetics advises testing for Spinal Muscular Atrophy (SMA). The American Society of Reproductive Medicine and the Spanish Fertility Society advise testing for X-Fragile Syndrome, an X-linked recessive disease that causes mental retardation in male children. The American Congress of Obstetricians and Gynaecologists also advise testing for Genetic Anaemia in African ethnicities.
Concerning the choice of going through treatment with donor eggs or donor sperm, the objective is not the test by itself, but the genetic matching to compare the genetic result of the two individuals involved to evaluate the reproductive risk. Also, to avoid having a child with a genetic disorder, but also not reject healthy carrier gamete donors. The matching between the donor and the recipient or the partner is the main goal of this type of testing.
There is a carrier partner or a carrier donor and a not carrier donor or not carrier partner, and this allows us to have a healthy child that could carry the disease or not, but it would be a healthy person.
- Questions and Answers
In my opinion, expanded carrier screenings offer the greatest benefit if performed preconception because it allows the patients, and the clinicians to assess the situation well, to know and assess the risks and to discuss clearly and freely the options without the pressure of already having a pregnancy developing.