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.
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.
This is a very good question and, in fact, no, it is not really possible to find a mutation in egg or sperm. You can analyze some things in eggs and sperm but a mutation – we have to find it in a genetic sample, blood or saliva, before obtaining the gamete or once the embryo is already created. We cannot analyze the mutations in eggs or sperm. No, it is not possible yet. What we usually do in our centre is we advise you to do an expanded carrier screening test to all of our patients. When we use our oocyte donor program, we always do the genetic matching between donors and recipients. When the couple is using their own gametes, we always advise them to do this expanded carrier test. We feel very comfortable with it and also patients.
Depending on the situation, we might advise doing a basic karyotype for the female patient. Clearly, we always do a karyotype for the sperm donor which is basic genetic testing and then we advise to do the expanded carrier screening test. Again, the important thing is not the results of the test but the matching with the best possible donor genetically.
This is a very interesting question. Here we’re talking about a slightly different situation which is when we do a PGT, a genetic pre-implantation test of the embryo, as you are well aware, we do the biopsy of the embryo on blastocyst stage. When we perform the biopsy, we remove part of this blastocyst tissue and then we vitrify, we freeze this blastocyst and wait for the results. Not necessarily a false negative. It’s just at some time, the result is not conclusive enough and we have to repeat the biopsy and, therefore, exactly what you were saying, we have to defrost the embryo and then freeze it again. Technically, we could do a double biopsy but a biopsy of an embryo is quite delicate – it’s an embryo, it’s a future being that is not very big so we have to minimize the amount of tissue that we remove from the embryo. Even though technically, it shouldn’t be impossible to do a double biopsy, we would never do it because most likely we will definitely have results with the first biopsy. We would risk damaging the embryo too much doing it twice at the same time if it’s not necessary.
This is a very interesting question. In fact, the answer would be yes and no. Some mutations are related to age, especially in females. As you all know we have a determined number of eggs at our birth and then we use them until they’re over. Men, on the other hand, continue producing sperm until they die, basically. The older we get the fewer eggs we have but also the more mutations these eggs might carry. Over 35, but especially over 40 the percentage of eggs that carry mutation is high but these are mutation linked to the number and shape of the chromosomes.
That’s why as age advances we are at higher risk of a miscarriage and at a higher risk of having a child with Down’s syndrome which means that your child has three copies of 21st chromosome. This is, however, not linked to the expanded carrier screening test because these Mendelian inheritance diseases are not linked to the age of the patient if you have a mutation you have since your birth. It is more secure to go through an egg donation treatment than with your own eggs for 40+ patients regarding malformations, Down’s syndrome and miscarriages but not regarding diseases such as cystic fibrosis or muscular atrophy, for example.
We do not force the patients to do it. We always like talking to our patients and decide together which is their best option but it’s definitely always advisable to be performed and almost always done. If you are asking if it’s included in the cost of the treatment, it depends but usually not. It is an extra cost because genetic analysis has to be performed.
Here we have a potential donor that carries a GJB2 mutation which is linked to genetic deafness. There’s actually quite a frequent disease that causes hearing loss, sometimes progressive, sometimes from birth which is not related to any other malformation or alteration and it’s genetic. It’s the most common cause of deafness in the world, genetically. This is what this potential donor could carry and then she carries metabolic disease in mutation which is phenylalanine hydroxylase deficiency. These two diseases are not life-threatening but, clearly, in this case, again you have this information of a person who carries two mutations. This is not what interests us. What interests us is if the partner carries these mutations or not. Your partner does not carry these mutations so usually what we do is we pass these results to a genetic specialist that assesses the remaining risk. Even if your partner is negative and the donor is positive, there is still a risk that the child could be born with one of those diseases. But the risk is usually really low. It depends on the type of tests that you performed because there are tests that are more thorough looking at the gene than others so I cannot really answer you to 100% with the information that I have.
But I think you could go ahead with the protocol without much issue. What we usually do in our centre, after genetic expert consultation, is we discuss the remaining risk with the patients so they can make a decision.
One in 20,000 possibility means that if you had 20,000 children one would be born with this disease. I think this is a risk that you should be able to assume. Of course, each person is different when we usually, for example, when we think about Down’s syndrome when we are pregnant and we do the first-trimester screening test which is done from blood and ultrasound assessment, they advise performing an invasive test such an amniocentesis when the risk is superior to one in 250. If you compare those data, you can see that one in 20,000 is really very low. In our centre, with this rate, we wouldn’t go ahead with this procedure. The risk is never zero.
No, I haven’t seen it but it’s technically possible. 1 in 19,000 means that one in 19,000 which is extremely rare and I haven’t seen it but it’s genetically possible. I would be very confident with this remaining risk. Honestly, I would go ahead with the procedure but then again there’s not a warranty that this won’t happen. The good thing with this situation that you have is that those diseases are not life-threatening. To sum up, when we start discussing numbers it might be a bit frightening. I think it’s good to have the information. I think it’s good that we all know that we all can carry diseases but the aim of these expanded key areas screening test is precisely to assess it better and to be able to be more relaxed, to be more confident about your chances of conceiving with a low or high percentage of a very healthy child. We have to discuss clearly the information with our patients so that they understand that if they have a risk that’s lower than one in 500 or one in 1,000, they can be very confident about the procedure. It’s better to know and to be able to detect it than not knowing.
