Genetic health in female and male reproduction

Roy Pascal Naja, PhD, DipRCPath
Laboratory Director, Eurofins Clinical Genetics UK

Genetics PGS / PGT-A, IVF laboratory, Success Rates

From this video you will find out:
  • How do genetics affect fertility?
  • What is the genetic basis of male sterility?
  • What causes chromosomal abnormalities in sperm?
  • Why is genetics important in prenatal development?
  • Does preimplantation genetic testing for aneuploidy really improve IVF outcomes in advanced maternal age patients?

What is the role of genetics in the reproduction?

In this session, Roy Pascal Naja, PhD, DipRCPath, Laboratory Director at IGENOMIX UK, who has talked about the role of genetics in female & male reproduction.

Roy Naja started his presentation by addressing the impact that genetic health has on male and female infertility. Humans were made of trillions of cells, and in each cell, there is one copy of the genome where there is all of a human genetic code or material kept there. This genome is divided into chromosomes, and these chromosomes are further divided into little subunits called genes. Those genetic subunits code, for example, eye colour, skin cells, the epidermis genes will instruct the body to form an organ and so on.

Genetic health – male factor

When we talk about male fertility issues, 2 major factors lead to male sterility, these are chromosomal defects and single-gene defects. Both of these defects will contribute to male infertility. A human should always have 46 chromosomes, or 22 pairs of non-sex chromosomes and a pair of sex chromosomes. In the case of males, there is 1X and 1Y chromosome, therefore, a karyotype of a human male is made of 46 individual chromosomes or 23 pairs of chromosomes where the sex chromosomes are X and Y.

We need to remember that sperm concentration is very important in male infertility, and you have to have 15 million of these sperm in 1 ml, and if a man has chromosomal defects, he’s going to have a problem with his sperm. 20% of all infertile men with sperm defects have chromosomal defects. Those genetic materials are chromosomes, and if you have a defect in your chromosome, you’re going to have defects in your semen.

There are two types of chromosomal defects, you might have a missing or an extra chromosome. A lot of cases of male sterility are attributed to Klinefelter’s syndrome in the category of chromosomal defects. This disorder means that the male patient has 2 copies of the X chromosome instead of 1 copy and 1 copy of the Y chromosome, which will lead to infertility or sterility. Therefore, many times when you go to a fertility clinic, you will be advised to perform a karyotype test. This test checks all your chromosomes, and if the karyotype shows that you have an extra X chromosome or an extra Y chromosome, this will explain the reason for your fertility problems.

Chromosomal defects can also be caused by structural events that happen in your chromosomes, this is called a translocation, and this also can cause low sperm count or no sperm at all. This happens when 1 chromosome sticks to another chromosome and vice versa. There might be a swap of genetic material between chromosomes 4 and 20, in such case a man is phenotypically normal, but when it comes to reproduction, he might have problems either with not being able to produce sperm or his sperm might have a form of structural rearrangement which will be shown in the karyotype.

Another common factor that leads to infertility in the male patient is something called Y chromosome microdeletions. When you go to a fertility centre, the clinician will ask for a Y chromosome microdeletion test besides the karyotype. If you have these microdeletions in your Y chromosome, then you will have problems with fertility, and you will probably produce very low numbers of sperm, which contributes to your infertility or sterility.

Single gene defects again lead to oligozoospermia, azoospermia or low sperm morphology, and/or motility. An example of single-gene disorders is Cystic fibrosis, Sickle Cell Anaemia, Beta-thalassemia or Myotonic Dystrophy. The most common type of single-gene disorder that causes infertility is cystic fibrosis which is a disorder that affects multiple organs in your body and this is fatal, at a certain point the patient might die because of suffocation or because he won’t be able to clear the mucus out of his lungs and the patient will give a respiratory arrest, plus if you have this disorder you’ll be infertile as there is the absence of vas deferens.

Other single gene disorders are Sickle Cell Anaemia and Beta-thalassemia, which are blood disorders, and these also affect your fertility or sterility.

Genetic health – female factor

Factors that lead to female infertility are again chromosomal defects, single gene defects, but also the status of your uterus or endometrium. The female karyotype is made of 46 individual chromosomes and 2X chromosomes.

If a female doesn’t have any eggs produced, she will be diagnosed as someone has an ovarian failure, you might have oocytes produced early on in life, however at a certain point prematurely, you will cease to produce oocytes. Chromosomal defects could be numerical, you could be gaining or losing a chromosome. The most common chromosomal defect is called Turner’s syndrome, a patient has only 1X chromosome, and the patient has deformities and very well-known physical characteristics but also infertility.

If a female patient has an extra X chromosome instead of having 2X chromosomes, this also contributes to infertility. If a female has got genetic material swapped in between her chromosomes, she also might have infertility. These translocation inversions or numerical abnormalities in your chromosomes are very common causes of infertility as well as single-gene disorders.

Single gene disorders that cause female infertility is fragile X chromosome, which is also a disorder that causes mental retardation or neurodevelopmental defects in certain females but also causes infertility. Sickle cell anaemia is another blood disorder that will require such a person to have dialysis to survive but also it affects fertility. Another common disorder is called Galactosemia, where you cannot digest sugars in your food, and this sugar level goes up and then causes infertility, these are just a few examples of many single gene disorders or defects in single genes that can cause infertility.

Another important aspect is the uterus or the endometrium because it has to be ready to accommodate this newly formed embryo. The endometrium also needs to have good bacteria, there are 2 places where bacteria are very important, and it is your gut to have good digestion and the uterus to accept the embryo and support the implantation. Sometimes, failed implantation occurs because you have bad bacteria in your endometrium. Some tests can check the receptivity of your endometrium and if there are good bacteria in your endometrium.

Genetic health – impact on the embryo

As the sperm fertilizes the egg, the embryo is created and this embryo migrates into a fallopian tube and needs to be implanted in the uterus. Once an embryo is created, it needs all chromosomes that a male or a female has, so if it’s a male embryo, you need to have 46 pairs of chromosomes where the sex chromosomes are XY, and for females, the embryo needs to have 46 chromosomes, and the sex chromosomes are XX. However, due to advancing maternal age, some chromosomes are lost or gained in an embryo, so an embryo might be missing, or it might have extra chromosomes, and this will lead to a failure of implantation or a miscarriage. This is the main cause of infertility. Advanced maternal age is one of the most important reasons that lead to female infertility, and this goes with age. These abnormalities in the chromosomes of the embryo go up to 85% in females that are of age 44-45, this means that only 15% of your eggs are good. If you have 10 embryos created at an IVF clinic, on average, only 1.5% of them are going to be good if you’re between 44-45. The solution for this can be a screening of such embryos to see if they are missing chromosomes or gained them. This test is called Pre-implantation Genetic Testing for aneuploidy (PGT-A).

When you go through the IVF cycle, you get your embryo created at the IVF clinic, then an embryo biopsy is done, where a very small piece of the embryo is taken, the embryo is frozen, this little piece of the embryo is put in a tube and then send to a genetics laboratory where it will be checked if this embryo has extra or missing chromosomes. If the embryo is abnormal, it is not going to be transferred, and if the embryo is normal, it will be possible to transfer this. This can help the patient achieve a healthy child, especially those of advanced maternal age.


- Questions and Answers

In which cases are genetic testing necessary for younger patients?

In repetitive implantation failure or miscarriage cases, patients should undergo genetic testing, and the clinician will ask for a Karyotype test regardless of age.

Is genetic testing necessary when doing a donor cycle?

If you’re seeking donor eggs and you’re at an advanced maternal age, the clinician might not ask for any genetic testing from you. Depending on the donor’s age, if it’s a young donor, the probability is that those eggs are going to be good, there’s not going to be gains and losses of chromosomes, and you might not need genetic testing.

Do you think pre-implantation testing will become the standard in the future for all cycles, regardless of infertility problems in the couple?

At the moment, I don’t think this is going to be common practice because the technique is very invasive and it’s very costly. However, in the future, there’s a lot of research where scientists are looking into creating eggs from something we call the stem cell, so from your skin. If you take a piece of your skin, you can produce eggs in a lab, and then you can fertilize this egg in a laboratory, you don’t need to stimulate the patient, so give the patient a lot of hormones to produce a lot of eggs, and it’s an invasive process, you go in with the catheter to collect these eggs.

All of this could be scrapped if we could create eggs from stem cells and then fertilize these eggs in a laboratory, and then you can just test these embryos, why not, and you’ll be able to test for many things in the future. I see it happening in the future if this stem cell technology is perfected. At the moment, not because this is a very invasive and costly procedure.

Could genetic testing be harmful to the embryo?

No genetic testing is not harmful to the embryo. What could sometimes be harmful to the embryo is the biopsy. However, many IVF clinics are very good and have experienced biologists that have perfected biopsying embryos, most times it will not cause any harm to the embryo.

Can you explain more about the test (ERA) used to analyze the status of the endometrium in case of failed implantation?

This test usually looks at the genes expressed in your endometrium, our test is the most common test available in the market. We look at 236 genes that have to be expressed in a certain way to make your endometrium receptive. You do this test in a natural cycle, the clinician takes a piece of the endometrium and puts it in a tube, and we do the genetic testing. This is done in your luteal phase or after your LH surge, or in a slightly medicated cycle.

Then we’ll test this in this endometrium or this piece of the endometrium, and it’s not a harmful process. You get local anaesthesia, and we’ll let you know if this endometrium is receptive, so if your window of receptivity is where it’s supposed to be, which is at day 19, and we’ll also tell you if your endometrium has the good bacteria to accommodate the embryo.

What are the alternatives to embryo biopsy?

At Igenomix, we’ve developed a test called non-invasive PGS or PGT-A (non-invasive Pre-implantation Genetic Screening (NI-PGS) where we don’t biopsy the embryo, we just take some droplets where your embryo is growing because the embryo is spitting out cells, and these cells will show 80% of the time if the embryo has gained chromosomes or lost chromosomes. It’s a non-invasive technique, we’ve just launched it last year, and it’s an alternative option for PGS.

How do PGT-A and the other types of PGT test account for mosaicism? 

Nowadays, we use something called next-generation sequencing (NGS), you’re doing PGT-A and NGS, or next-generation sequencing is very sensitive, it can pick up mosaicism. We found (this is internal data) that only 5% of the time the embryo is mosaic, meaning we’re not sure if the embryo has an abnormality or not, only 2.8% of the time, this embryo will have a low level of mosaicism.

This embryo is given a chance to be transferred, but before transferring this embryo, the patient will undergo genetic counselling where the genetic counsellor will explain the risks of transferring a low mosaic embryo, but that’s only 2.8% of the times.

Is this non-invasive technique as good as PGS?

It’s different, it’s not diagnostic, it’s a test that gives priority to the embryo, so if you have 4 embryos produced in an IVF cycle, and we do this non-invasive PGS, it will give you the answer on which embryo is best. For example, embryo number 4 is the best, embryo number 2 is the second-best and so on.

It gives a chance for every embryo to be transferred, so that’s its advantage over PGS, but it’s only 80% sensitive compared to PGS. PGS will give a more precise answer to whether you have lost or gained a chromosome. There’s pros and cons for non-invasive PGS.

Does genetic testing create designer babies?

It’s important to understand the difference between choosing what ended up from the parents into the embryo. For example, if mom has a genetic disorder, mom has a 50% chance of passing this genetic disorder to the embryo.

When you do PGT or the pre-implantation genetic testing, you screen for the good gene of mom, which 50% of the time statistically is passed onto the embryo. We’re just looking at what ended up in the embryo, and we’re not changing anything in the genetic makeup, so if you’ve heard of gene editing, then it’s actively changing your genetic material, and then you’ll have designer babies, but with PGT there are no designer babies.

Do fibroids have to do with some female genetic issues?

Certain studies suggest some patients with some gene defects are more prone to develop fibroids, but usually, these fibroids are not caused by genetic issues. Once they’re removed, they should not cause any infertility leiomyomas.

When is DNA fragmentation testing necessary?

Sometimes a very bad lifestyle, lots of smoking and drinking alcohol will lead the DNA to fragment in the sperm. There are certain cases where the clinician will ask for a DNA fragmentation test to see if it’s elevated as compared to a normal person.

Some studies associate a high DNA fragmentation with chromosomal abnormalities in embryos. The clinician will ask you about your lifestyle and diet, and sometimes they will ask for DNA fragmentation to be done.

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Roy Pascal Naja, PhD, DipRCPath

Roy Pascal Naja, PhD, DipRCPath

Dr Roy Pascal Naja has more than 20 years of experience in clinical diagnostics and health care management, with a focus in fertility. Before joining Eurofins Clinical Genetics UK in 2023 as Laboratory Director and CSO, Dr Naja was the Laboratory Director at Igenomix UK from 2017 to 2023. Prior to this, Dr Naja held several Principal/Senior Scientist positions in private healthcare, NHS and university settings. Dr Naja is a Clinical Scientist (HCPC) and a “Diplomate” member of the Royal College of Pathologists. Dr Naja is a technical expert with the United Kingdom Accreditation Service (UKAS). Having a strong research background and a PhD in Human Genetics, Dr Naja maintains an Associate Professorship position (Honorary) at the department of Reproductive Health, University College London.
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