Understanding the Importance of Carrier Genetic Testing

Dr José Félix García España
Fertility Specialist & Medical Director , UR Vistahermosa

Genetics PGS / PGT-A

From this video you will find out:
  • What is Carrier Genetic Testing?
  • What is the difference between a basic panel and an extended panel of carrier genetic testing?
  • What common genetic disorders can carrier genetic testing detect?
  • How does genetic matching between donor and recipient work?

Understanding the Importance of Carrier Genetic Testing

During this event, Dr José Félix García España, Medical Director of UR El Ángel, explained how
carrier genetic testing can help identify individuals who carry a gene for a genetic disorder that could be passed to their offspring. Dr García España shared the information about the benefits and implications of the carrier screening.

Understanding Genetic, Chromosomal, and Congenital Problems

When a baby is born with a defect, it’s often mistaken as chromosomal problems, genetic problems, and congenital problems; however, these need to be differentiated.

Chromosomal issues occur when the baby has an abnormal number of chromosomes. Every human has 23 pairs, 46 chromosomes in total. Sometimes, a baby comes with one chromosome more (47 instead of 46) or one less. For example, Down syndrome is when a baby has three chromosomes in pair 21, so the whole chromosome is duplicated.

Congenital problems are not genetic or chromosomal issues; for example, a cleft palate or cleft lip occurs during the growth of the baby inside the uterus, without a chromosomal or genetic cause. Genetic problems mean there is a molecular defect inside 1 of the chromosomes. For example, a person with cystic fibrosis has all 46 chromosomes, but one of the chromosomes has a small molecular defect that causes the disease.

When we talk about genetic problems, we may come across three situations:

  • Dominant diseases mean the disease is always present. For example, if the husband knows he has a disease and the wife is healthy, 50% of their children will have the problem, and 50% will be healthy.
  • There are also recessive diseases, which means that someone may have received a bad gene from the mother for cystic fibrosis and a good gene from the father, so that person is a carrier but is a healthy human being. However, a person can carry 1 gene with the disease, but cystic fibrosis is not present because the good gene covers the bad one. Suppose a wife has the same problem and is not aware of this because she is healthy. In that case, her children may have different combinations: 2 good genes (healthy baby), 1 good and 1 bad gene (healthy carrier baby), or 2 bad genes (baby with cystic fibrosis). This explains why a couple may have 4 babies: 3 healthy and 1 with the disease.
  • X-linked recessive diseases are tricky because women are carriers, and men suffer from the disease. The molecular problem is on the X chromosome. A woman has 46 chromosomes, with 2 X chromosomes, while a man has 1 X and 1 Y chromosome. A woman may be a carrier of haemophilia, a disease where you start bleeding and can’t stop. Women have 1 healthy X and 1 X with the disease, so they don’t present the disease. However, if the woman is a carrier and gives the bad X chromosome to her child, and the husband gives the Y chromosome, the child will have the disease because there is no second X to compensate. That’s why haemophilia is carried by women and suffered by men.

This is one of the reasons why the carrier panels are important. Nobody knows that they are carriers. It’s said that normally 80% of the population may carry one of these 1,000 conditions. It is estimated that there are about 1,300 chromosomal genetic problems like this, and it’s normal to be a carrier of something. The problem is meeting a partner, woman or man, who is carrying the same thing.

Genetic Carrier Screening – what is it?

Genetic carrier screening helps to identify high-risk people. There are 1,300 conditions with recessive and X-linked inherited diseases. It means that 3 out of every 1000 newborns are affected by these conditions, and 2-3 out of every 100 couples are of high genetic risk. This means it’s not sure which couples are at risk, and they don’t know if they have one of these 1,300 diseases that may happen.

Why being a genetic carrier is a problem? It’s because approximately 1 in 300 pregnancies results in the baby having 1 of these genetic diseases. Down syndrome occurs in 1 in 800 pregnancies (it increases as the woman’s age increases), and open neural tube defects like spina bifida occur in 1 in 1000 pregnancies. The probability of having a baby with spina bifida, or cystic fibrosis, is much higher than having a baby with Down syndrome.

That is where the genetic carrier screening panel comes in, but is it possible to screen for more than 1000 diseases? No, that is why, it has to be selected.  Every international society has its guidelines to recommend which ones and what number should be convenient.

We have to select groups of panels where these diseases we check should be severe, universal (not concentrated in one particular area of the world), easily identifiable by the symptoms, and, of course, with no treatment available. If we talk about a disease that can be treated and the baby is fine, we assume that is not a big problem as if there is no treatment at all. I always say to my patients that more money should be invested in these rare diseases, probably because once the baby is affected, it’s going to be very difficult.

Genetic panel selection

There are 2 panels available, nowadays: the basic panel with 38 diseases or genes, including 15 or 16 genes that both the husband and the woman should carry, and the X-linked genes, which are hidden in women and can be passed on to a baby with a problem.

In the extended panel, 552 genes are studied. Normally, the basic panel is chosen because these diseases are concentrated in those with a higher prevalence in the population. In contrast, with rarer diseases, it’s less likely for patients to share the same issue, making it more challenging to match them.

The basic panel includes diseases such as beta-thalassemia, Fanconi Anaemia (FA) – a form of anaemia, Tay-Sachs disease, spinal muscular atrophy, and cystic fibrosis. For instance, cystic fibrosis affects one in 28 people worldwide, increasing the chances of a carrier couple having a child with the disease to 25%.

X-linked diseases are included in the panels for both female and male donors, such as those involved in egg donation. Screening is conducted before donation to ensure that donors do not carry severe genetic diseases.

Screening should be done before starting a reproduction cycle. Patients should be informed beforehand to avoid any misunderstandings. If a baby is born with a genetic issue after undergoing treatment, the responsibility cannot be placed on the reproductive unit if the parents were not informed about the available panels.

Genetic Matching

Genetic matching aims to ensure that both individuals in a couple do not share the same genetic issue, which means there is no option for transmission of these diseases to their offspring. This process includes the verification of whether each partner carries distinct genetic conditions.

Pre-pregnancy testing is crucial, as genetic diseases cannot be checked once a woman is pregnant. Ultrasound scans can detect congenital defects, but genetic panels must be studied before pregnancy to identify any genetic issues.

If there is a pathogenic mutation, then we study the male. If the male has no mutation, then there is low risk. If a woman has a problem and the male has a mutation, then what do we do? If both of them have the same problem, they are healthy carriers but carry the same thing. In that case, we may do IVF with a biopsy of the embryos to see which ones have inherited both bad genes from the mother and the father. Alternatively, they may choose to use donor gametes or sperm donation.

Donor-Patient Study

At Vistahermosa, all donors have to undertake basic panel screening. As a result, if the donor has a pathogenic variant of one gene and the male of that couple doesn’t have the same mutation, they are compatible because they are not going to have that problem. The couple will not have a problem, the baby will be healthy, and that donor may give her eggs to that couple.

However, there might be a donor who has a pathogenic variant and the husband, the male of that couple, has the same problem, in that case, they are incompatible after the genetic match, that means, another donor needs to be selected.

What happens if the donor has one of these variations of X-link? In such situations, such a woman cannot be a donor. She may give an X chromosome with the problem, and if the baby is a baby boy, he will have the problem, and the husband has nothing to do with this. When something like this is discovered, they are informed about such issue, they cannot become donors, but it doesn’t mean that they cannot be a mother in the future. However, if a woman wants to get pregnant, she needs to inform her doctor about this in order to do IVF with genetic biopsies PGT-M in this case because we are looking for one special mutation.

Key Points

  • Pathogenic mutations require studying the male partner.
  • If both partners are carriers of the same mutation, options include IVF with embryo biopsy or donor gametes.
  • Donors are screened for pathogenic variants to ensure compatibility.
  • X-linked variations in donors automatically disqualify them.
  • Screening reduces the risk of unexpected rare diseases in babies by 47% to 90%.
  • Screening is a precautionary measure, not a diagnosis.
  • Not all rare diseases are screened due to rarity and manageability.
- Questions and Answers

How often do you need to tell the donor that they cannot become a donor after the testing? 

I don’t have the exact numbers, but I can estimate. I probably manage about 30 donors per year. They may donate several times, but at least 2 or 3 times a year, I have to inform someone that they can’t donate. This is just an estimate, as I don’t have the specific numbers. One of the most common ones is Fragile X syndrome. This happens when a piece of the X chromosome is missing, and with each generation, the problem becomes more severe until one generation shows significant symptoms. This condition happens quite often, and we have to check for it, especially in women who have a low egg reserve. It’s one of the key things we need to monitor. These conditions are not uncommon at all.

Is there an option to customize the carrier screening panel based on your personal or family medical history?

Yes, there is. For example, today I saw a couple with a specific problem. In that case, we are not talking about a standard panel. This particular patient mentioned that her nephew had a problem. When he was investigated, they did a panel and discovered that the family were carriers of several different things.

She couldn’t recall which specific condition it was, but it became important because it was discovered that her brother and the patient were carriers of something. In such cases, I would contact our genetic department and inform them that I have a woman who is a carrier of a particular mutation. They would then study her husband for that specific mutation. This isn’t a standard panel but rather a targeted approach based on the specific problem.

Sometimes, we start with a basic panel. For instance, if we discover that a woman is a carrier of alpha thalassemia, instead of having the husband undergo the entire panel, the genetic lab will study only for alpha thalassemia in him. This approach can be more economical, since the important thing is to ensure that both partners don’t carry the same genetic condition.

What should patients expect in terms of understanding the results? Are there common misunderstandings or confusions?

Normally, it’s quite clear because we don’t get into overly complex explanations. It’s very straightforward. For example, if you’ve done the panel and there are no mutations, I simply say, “Okay, you’ve done the panel, and you’re fine. No mutations.”

If there are one or two mutations, I explain, “You will never have this disease. You are just a carrier.” This reassurance is important because many people are carriers of something, and it’s good to know. The next step is to study the husband. If he doesn’t carry the same mutation, there is no problem. The main concern for patients is ensuring their children don’t have the disease, and we make that very clear.

What are the limitations of the screening panel?

As far as I know, they tell you that this is a 99% point of certainty because they didn’t explain and go into these lab methods of how they work with that, but normally they study practically the whole gene with all mutations. That’s why sometimes if the gene is very, very large, they may start studying the most frequent mutations and the less frequent ones may not be studied. The whole gene cannot be studied, and some mutations are very rare. And if they are very, very rare, it’s rarer that both of them have the same problem.

Would genetics issues be the cause of repeated implantation failure? What issues with genetics could cause implantation failures?

These diseases shouldn’t be related to that problem.  We are talking about the problem of a baby who has been born and has a genetic disease, okay? So, the chromosomal things are more involved in miscarriage and implantation failure. That’s why ESHRE is recommending the PGT-A because discard that we are transferring embryos with chromosomal problems but not genetic diseases.

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Dr José Félix García España

Dr José Félix García España

Dr José Félix García España is a Medical Director of UR El Ángel since 2011. He obtained his Bachelor of Medicine from the University of Malaga. After finishing his studies, he worked in emergency medicine, until starting the speciality of Gynaecology and Obstetrics in the United Kingdom in 1992. During his training he worked in several hospitals, highlighting the University Hospitals of Withington and St Mary's in Manchester. At this stage, he passes the examinations of the speciality. He is a member of the Royal College of Obstetricians and Gynaecologists (RCOG). Back in Spain, he worked as a reproduction specialist at the Gutenberg Center for 14 years.
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Caroline Kulczycka

Caroline Kulczycka

Caroline Kulczycka is managing MyIVFAnswers.com and has been hosting IVFWEBINARS dedicated to patients struggling with infertility since 2020. She's highly motivated and believes that educating patients so that they can make informed decisions is essential in their IVF journey. In the past, she has been working as an International Patient Coordinator, where she was helping and directing patients on their right path. She also worked in the tourism industry, and dealt with international customers on a daily basis, including working abroad. In her free time, you’ll find her travelling, biking, learning new things, or spending time outdoors.
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