Genetic health in female and male 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.