Genetic carrier screening in our egg donation program

Gemma Castillón Cortés, PhD
Fertility Specialist & Deputy Director
Genetic Carrier Screening in our egg donation program #OnlinePatientMeeting
From this video you will find out:
  • What is the Carrier Screening Test?
  • Who is the Carrier Screening Test for?
  • I am a healthy person. In my family, there is no history of genetic diseases. Can I be a carrier of genetic mutations?
  • But, these diseases are rare, so is it necessary to perform a Carrier Screening Test?
  • Will my children be carriers of recessive genetic mutations?
  • My partner performed a genetic compatibility test in a laboratory and the egg donor has done a carrier screening test in another
    laboratory. Is the first test that my partner did still valid for use?
  • Is there any residual risk after having this test done?
  • If I am a carrier is it desirable for people in my family who are planning a pregnancy to conduct a carrier screening test?


Everything you need to know about genetic carrier screening

Gemma Castillón Cortés, PhD, Deputy Director at IVI Barcelona, is discussing genetic carrier screening in egg donation programs.

- Questions and Answers

What is a carrier screening test?

This is an important genetic test when you’re planning to have a family. It will help you to determine the risk of having a child with a genetic disease. This test will let you know if the parents carry a mutation in the same gene if there is a risk of having an affected child – this is prevention. Generally, parents only realize they’re carriers of serious genetic disorders after the affected child is born and the global prevalence of this disorder is 10 in 1,000 live births so it’s important to get this knowledge. Anyone, even me, without knowing can be a carrier of one or more mutations. To our knowledge and according to the studies we have done the average carrier is 2.3 per person. In our study, that was published in 2015 when we started doing this test we found that in 5% of the couples a carrier of the same condition can be found. So they will be at risk of having an affected child.

Who is the carrier screening test for?

As I said before we all have changes in our genes so the test can be recommended in all these cases. Firstly, if you are thinking about getting pregnant naturally; secondly, this test can be done before assisted  reproduction treatment to determine the best type of treatment, and, thirdly, before treatment with donor sperm or eggs. In this case, you ask your doctor to do this test because you want to be able to select a donor that doesn’t carry the same mutation as the people who will provide the gametes, the egg or the sperm. This indication is the most common indication in our day-to-day practice in our clinic. In my experience, 60% of my patients when they are recipients of donor eggs, choose to do the carrier screening test before finding a donor.

I am a healthy person. In my family, there is no history of genetic diseases. Can I be a carrier of any genetic mutations?

Definitely, yes, and that’s an important question because when I’m talking to my patients about that option, they always ask me this question. They say that they’re healthy and they have no family history of diseases. I say, yes, but the carriers are always healthy people when asymptomatic and they aren’t aware of this condition until this test is done or if they have an affected child in a past pregnancy. Moreover, the carriers don’t have a family history of a genetic disease so this fact alone is not valid to determine whether another person is a carrier of a mutation that can be transferred to the offspring by just keeping in mind the family history. Being a carrier is not the same as getting the disease. That should be clear because it’s the first point to move forward.

Genetic diseases are rare so is it necessary to perform a carrier screening test?

Genetic diseases are relatively rare. Every year, 8 million children are born with a severe single genetic disorder – this data has been published in 2014 and in a general sense it is estimated that genetic conditions have a global prevalence of around 1 in 100 or 10 in 1,000. The prevalence of carriers is quite common in some populations, for example, 25 people in 100 are carriers for cystic fibrosis or spinal muscular atrophy, just to let you know some examples of genetic single genetic disorders.

Will my children be carriers of recessive genetic mutations?

The answer is yes. When two people carry a mutation in the same gene, they have a 50% chance that their children will be carriers of a genetic mutation. 25% of them will not be carriers and 25% will be born sick. Moreover, when there is a person that is a carrier of a genetic mutation and the other person is not, the probability that their children will inherit the mutation of the surrogate parent is 50% and the chance of not inheriting it is also 50%. But the most important thing to take into account is the first part of the explanation: if both members of the couple have the same mutation in the same gene, they have a 25% chance to share a genetic disorder with the baby. It is quite high.

My partner had a genetic compatibility test done in the laboratory and the egg donor has done a carrier screening test in another laboratory. Is the first test that my partner did still valid for use?

It’s a quite common question because more and more patients find a different  kind of screening genetic tests in different labs and when they come for a visit, they ask the question “can I use the tests I did in the past?” And the answer is not straightforward because the karyotyping test uses its own technology and the number of mutations in some diseases that are included may vary between them so the answer will depend on the result. And that is what we have been doing with our donors. We do ECG from Genomics and then if the gene is present in both tests and the number of mutations in this test is similar the genetic matching may still be an option. However, if the gene that is altered in the patient is not present in our own test and all the percentage of mutation is so different, we will need other options such as to sequence the whole genome with an expanded test. I think it’s not easy to understand but the message should be that we always try to do our best, to make the most of the test that the patient can give to us.

Is there any residual risk after having this test done?

I would like to say no because it’s quite good technology but, yes, there is a residual risk. Currently, on the market, there is nothing to detect all existing mutations of each gene. That is not possible nowadays. The sensitivity is around 90-95% and also there can be a situation where even if you’re not a carrier of the mutation confirmed by a blood test, you may have some disorders in the germline cells. And, of course, if you are negative for a mutation, it doesn’t mean the embryo can have some new mutation in the embryo generation. So I’m so sorry to say that, yes, there is a residual risk but it’s true that in any of the severe genetic disorders the risk is reduced to 1 in 30,000. We are starting 1 in 1,000 and now we are in 1 in 30,000. It’s much better.

If I am a carrier, is it desirable for people in my family who are planning pregnancy to have a carrier screening test done?

This is also a quite common question. When you give the result to your patient with some disorders, because as I said, the average is around 2-3 mutations in each person, even me if I do the test, so if you’re a carrier, your immediate relatives may also be carriers. Therefore, sharing this result is advisable to provide them the opportunity to seek genetic counseling, that is my point. I know that this is quite hard to ask the patient to share these results with their relatives when they don’t speak so much with them about reproduction and treatments. But it would be good advice to share the results and try to help their relatives to know more about planning their own families as well.

My husband’s mother has a genetic disease but my husband doesn’t have it. It looks like not all his siblings have it. In that case I guess the genetic screening is needed since we would like to use his sperm for egg donation.

If your husband’s mother has a genetic disease and all his siblings have it, this is not a recessive disease. This is a dominant genetic disease that is quite severe. Even more, than we are talking about today so definitely your husband and you need a genetic counselor that will know everything about whose relatives have been affected, which of them have not been affected and they will offer you the diagnosis of dominant genetic disease or the need for a carrier genetic test for recessive mutation. I consider it quite important to do this counseling before you go ahead with the egg donation. As we said at the beginning, it is more important to prevent and, prevention is even more important when you cannot cure a severe genetic disease.

Can you repeat the carrier percentage in the general population and the risk if both people share the same mutation?

We published that in 2015 in the “Fertility and Sterility.” We analyzed 138 couples and we found that 5% had bad luck – what I mean is when you share with your partner the same mutation; so you are in the situation of having a child with a severe genetic disorder of 25% chance. At least, it’s more than I expected.

Is genetics testing standard in your egg donation programme? Would it be beneficial to test my partner’s sperm as well? Are these included in the price packages or are they extra?

Is genetic testing in your egg donation program? Yes. We really believe in that tool. It’s even in the legal framework. As doctors, we should, at least, inform patients about the level of technology that we have to avoid these genetic disorders. So, yes, the answer is definitely yes. Will it be beneficial to test the partner’s sperm as well? Yes, because then you will be in control and you will know if the donor that has been selected for your physical traits according to the law, and your partner share the same mutation if they are in this 5%. Yes, for me, it’s always working. Of course, the genetic screening test, ECG from Genomics that we do is not done on all our donors so we exclude, for example, donors with the X-fragile that is supposed to be 0.8 of our donors so even we do a prior good job selecting the best donor for you, I think it is useful given the risk that you are in 5% of sharing the same mutation. Is it included in the price? No, this will be an extra payment but it will be clearly explained.

Both my husband and our potential egg donor are carriers of certain genetic diseases in the 301 panel at Invitae (288 general panel plus 13 add-on genes) but neither have the same ones, thankfully. What is your opinion on getting a potential surrogate tested so she doesn’t have any of the same carrier conditions as my husband and the donor and does not accidentally turn on the genes of these carrier conditions in any baby she will carry for us, through epigenetics?

I suppose that the patient is worried because the number of diseases included in that panel are 301 and, for example, in this test that we use, Genomics ECG, we include 545 genes. I think the question is if I go through the panel with more mutations included… I can tell you that the most common ones are included in all the panels so maybe I think it is enough what you are doing. I think that you are more in control than the general population and even more than couples experiencing spontaneous pregnancies so I will say don’t get stressed. You have done a lot. Now about epigenetics – I would say epigenetics is quite important but I would say always can be positive thinking about the effect that you are going to produce in the embryo from the beginning. We did very nice research with one of the doctors – the very beginning of his research where it was shown that the intended mother, you, not the donor, you are going to send your RNA that will interact with the embryo in the very early stages of the implantation. You will get some epigenetic effect on that embryo. So the healthier you are the better for your embryo from the beginning. Should you test the surrogate? No, the surrogate is not going to give any genes to the baby. But, yes, it’s true that will have some effect in epigenetics with the exosomes and the RNA that can be affected the gene expression. However, this is under research. You have so much to worry about nowadays so I think you shouldn’t worry about this.

In order to prevent de novo mutations in the process, is it possible to do a PGT-A in Spain and a double donation? Is it legal?

To prevent de novo mutations, you cannot do any tests to prevent them because always when you try to diagnose mutations in embryos, you should have a map beforehand. So you should know what you’re looking for. It is possible to do PGT-A – that is different because we are talking about the control of the number of chromosomes in the embryo. In the same way, we can do PGT-A in women over 38 with repeated miscarriages or implantation failures. In a double donation, we will have to do it with an indication. It means that if we have a double donation with miscarriages or implantation failure, we can do it. If not, we cannot do it because there isn’t any indication to apply a selection for chromosomes.

How can we make sure that the egg donor is not carrying any genetic disease? I  know they are tested for that but is it 100% reliable?

No, you cannot make sure the egg donor is not carrying any genetic disease if you are talking about the 5,000 genetic mutations we can have as humans. What you can have is a test studying 545 genes for 600 genetic diseases. Some of them are quite common, as we said e.g. cystic fibrosis – the carrier prevalence is 1 in 25 order and other less common diseases. So I think that the answer is you will never have the 100% security of having a baby without any genetic disorder but, at least, you can test for the most common ones. Of course, as I was explaining in my third answer, yes, there is a residual risk if you consider de novo mutations. Nobody can check for that. Yes, there are some improvements in the genetic tools but at least we have some tools that they are working very well in a very good number of disorders.

Is it possible to find out about any mitochondrial diseases with PGT? I asked this before but it wasn’t really clear to me at that time since English is not my mother tongue. My son is suffering from Leigh syndrome and I’m planning to have another child. I’m the carrier and it was de novo mutation in my son’s case. We only found out when he was 18 months old, even though he had it already when he was an embryo.

This is exactly the situation that we want to prevent when we’re talking about genetic diseases. How are we working with mitochondrial diseases nowadays? In Spain, it is not allowed yet but, for example, in the UK, they do it. The mitochondrial diseases are in the egg. What we can do is to take a donor egg and do a nuclear transfer. Your genes are in the nucleus of your egg and these give your kid all the physical traits and all your genes but we don’t want the genes you have in your mitochondria. So what the labs are allowed to do because of the legal framework is to take out your nucleus and transfer this nucleus to the egg of the egg donor without her nucleus. So you keep most of your genes. The only genes you’re losing are your mitochondria genes and you will never have the genes from the donor. This is nuclear transfer; it is allowed to do in your case for your second child. My recommendation for you is you should talk to your reproductive medicine counselor/biologist. You will understand exactly the heritage of the mitochondria and they will explain to you how the nuclear transfer works. You will need an egg donor but in a different way than we are used to.

I heard about nuclear transfer but this procedure is far too expensive for me.

I know. I think we are closer to a systematic treatment all around the world. There’s a great job done by three groups in Europe so I hope this procedure will be one day a day-to-day clinical practice and then it will be less expensive, that is my hope.

Regarding the 5% residual potential carryover even if I test my surrogate and the epigenetics where the RNA of the gestational carrier can have the potential to influence what genetic traits the baby already has in their DNA and how it is expressed, is there something else to worry about?

I know that you’re worried about genetics and I understand that. Researching epigenetics is quite a challenge. In our research, what we studied was how the RNA from the mother can affect the appearance of the embryo into  the implantation. Imagine that we are quite far away of knowing in which conditions this RNS can affect the embryo. We consider that this is going to be related to their general health, for example, metabolic syndrome, some disorders in hypertension, diabetes – this can be RNA transmitted epigenetic disease. I will say don’t get stressed and worry about that if the surrogate mother is quite healthy. I suppose this is under control because every party wants the best.

If the donor had been tested and the sperm had been tested, would you recommend testing the embryo as well?

Let’s focus on the two issues that are in your question. If the donor is tested for gene mutation so let’s try a different concept: in our cells we have 46 chromosome couples. We are saying that the egg donor has been tested for any mutation in the gene so in very small pieces of the chromosome. The sperm has been also tested for the same gene mutation. The same test looking for the same mutation in the same gene. Would you recommend to test the embryo looking for gene mutations, for monogenic genetic disorder? The answer is no. But if you are asking me to test the embryo for the number of chromosomes what is called a PGT-A so then it could be done. It depends on the concentration of the sperm because of a severe male factor when you have less than 5 million sperm. My thesis was about how that is going to increase the number of disorders in the number of chromosomes. I will say no testing the embryo for genetic disorders and mutations; it will be tested for chromosome.
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Picture of Gemma Castillón Cortés, PhD

Gemma Castillón Cortés, PhD

Gemma Castillón Cortés, PhD, has been a gynaecologist specialist in Assisted Reproduction at IVI clinic since 2003 and a Deputy Director at IVI Barcelona since 2010. Gemma has been a Member of the Spanish Fertility Society (SEF) since 2009, Member of the Catalan Society of Gynaecology and Obstetrics (SGOC), Member of the Organizing Committee of the Endocrinology and Reproduction Section of the SGOC since 2010 and a Member of the MSF team (Médecins Sans Frontières), since 2015. Among her extensive medical training she holds a Master’s Degree in Laparoscopic Surgery, Master’s Degree in Research in Management Science at ESADE, Barcelona 2009-2011, PhD in Medicine and Surgery, where she wrote on “Prospective and randomized study on the utility of CGH Arrays for the study of embryonic aneuploidies in severe male factor.”
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