INFERTILITY DIAGNOSIS Article · 17 June 2022

Genetic infertility – a dictionary of the most important tests

Couples with fertility problems often visit many specialists and do dozens of tests. It is worth remembering that genetic factors are considered one of the most important causes of infertility. What genetic tests should you do if you have fertility problems? Check!

genetic infertility

Couples with fertility problems often visit many specialists and do dozens of tests. It is worth remembering that genetic factors are considered one of the most important causes of infertility. What genetic tests should you do if you have fertility problems? Check!


Karyotype test


The karyotype test is the basic test recommended for couples unsuccessfully trying to get pregnant. They are made from in vitro cultured peripheral blood lymphocytes from both partners. Karyotype examination can detect abnormalities in the number or structure of chromosomes. It is worth knowing that in a single cell of a healthy human body there are a total of 46 chromosomes organized in 23 pairs. However, this number is not always correct.


Chromosome aberrations


The abnormal number of chromosomes in a given couple in a karyotype is called aneuploidy. Aneuploidy is a chromosome numerical aberration. Sometimes, e.g. due to abnormal chromosomal disintegration during cell division, structural chromosomal aberration occurs. It involves changes in the structure of individual chromosomes. Fertility disorders may result from parents carrying a number or structural chromosome aberration. Balanced translocation (there is no loss of genetic material in the genome) usually does not cause any symptoms to the person who is its carrier. However, it can cause fertility disorders resulting from the effect of chromosomal translocation on the effect of meiotic divisions during gamete formation.


Methods of karyotype testing


Chromosome aberrations responsible for infertility can affect both autosomes, i.e. non-sex chromosomes, and sex chromosomes. Two techniques are routinely used to detect changes in chromosomes: GTG karyotype and fluorescence in situ hybridization (FISH). A more advanced method of karyotype testing is the technique of comparative genomic hybridization to microarrays (array CGH, aCGH). It is used to determine the number of copies of DNA fragments in the genome (CNV), i.e. to identify changes in chromosomes that are problematic for classical cytogenetics. The aCGH method makes it possible to identify the imbalance of a given genome fragment (e.g. aneuploidy, deletion and duplication) with precision previously unattainable by other methods of classical cytogenetics. The karyotype assessed by this method is called molecular karyotype. The limitation of the aCGH method is the inability to detect balanced chromosomal aberrations and polyploids, i.e. situations where there are more than two chromosomes in the karyotype.


Genetic syndromes and infertility


Among others, the genetic cause of azoospermia in men may be Klinefelter syndrome. This disease is caused by the presence of at least one additional X chromosome in the male karyotype (47, XXY). Klinefelter syndrome may also have the form of a mosaic. Some of the cells then have the correct chromosome arrangement, while some have an additional X chromosome.


Lack of X chromosome X


Turner syndrome (TS) is a genetic disease involving the partial or complete absence of the X chromosome in a female karyotype. The clinical phenotype of a woman affected by TS may be different because it depends on the type of change in the patient’s karyotype. In Turner syndrome we can observe monosomy X chromosome (50-60% of patients with TS), mosaic type karyotype, in which some cells have two sex chromosomes, while only one (20-30% of patients with TS, most often 45, X / 46, XX and more rarely 45, X / 46, XY) and structural changes involving the X chromosome, of which the presence of the long arm X chromosome is most often observed (5-10% of patients with TS).  A small percentage of cytogenetic diagnoses are other, more complex karyotypes in the mosaic pattern with the 45, X line and with structural changes in the X chromosome in the form of partial or complete deletion of the short arm (2%) or long arm (<2%) of the X chromosome, or occurrence X-ring chromosome. In patients with X-chromosome monosomy, we observe gonadal dysgenesis and therefore infertility. The fertility of patients with a mosaic karyotype or with structural changes within the X chromosome depends on the characteristics of this karyotype or type and location of structural aberration.


CFTR gene testing


Mutations in the CFTR gene are responsible for the development of a very serious genetic disease called cystic fibrosis. Why are we talking about it in the context of infertility? Because in addition to problems with the respiratory system, this disease can cause obstruction of the vas deferens in men – already in the fetal period they become clogged with thick, sticky mucus. Sometimes a man is completely deprived of them. For women, cystic fibrosis can contribute to the thickening of cervical mucus, making it difficult for sperm to migrate towards the egg.


Testing of the AZF region on chromosome Y


This region includes genes that code for proteins involved in the process of spermatogenesis, i.e. the formation of new spermatozoa. The loss of a small section of this region (microdeletion) causes the production of male gametes to be disturbed. This leads to azoospermia or severe oligospermia, which in practice means either a complete lack of sperm in the ejaculate, or at least a decrease in their number.


Examination for congenital thrombophilia in a woman


The presence of congenital thrombophilia in a woman contributes to infertility and habitual miscarriages. The body is then more susceptible to thrombosis and related complications – pulmonary embolism, stroke or heart attack. Congenital thrombofillia poses a special threat to pregnant women. Increases the risk of miscarriage and can inhibit fetal growth. Congenital thromobfilia has a genetic basis and may be the result of several genetic mutations – most often it is caused by a Leiden factor V (F5) and prothrombin gene (F2) mutation. Congenital hypercoagulability does not always give visible symptoms. Ladies usually find out about its existence only when they have another miscarriage or have problems conceiving a child. Interestingly, thromboembolic changes can also reduce the quality of sperm in a man.


Effect of several genetic mutations


In the diagnosis of congenital thrombophilia, in addition to factor V Leiden and the prothrombin gene, analysis of the R2 variant of the F5 gene and the promoter of the plasminogen-1 activator inhibitor (PAI- + 1) gene are also often included. Until recently, genetic diagnostics of the MTHFR gene was carried out, however, the latest scientific studies show that polymorphic changes c.665C> T and c.1286A> C in the MTHFR gene have a low predictive value in the diagnosis of the causes of reproductive failure and in the diagnosis of thromboembolic disease. At present, a more promising genetic marker related to the successful implantation of the embryo in the future placenta is the evaluation of the PAI-1 gene promoter.


Genetic tests for infections of the genitourinary system


Infections of the genitourinary system are a consequence of the penetration of viruses and bacteria into the human body. Infection usually occurs during sexual intercourse with an infected person, but also through contact with their saliva or blood. Failure to treat urogenital infections may result in pregnancy loss and infertility. Genetic diagnosis of infections of the genitourinary system consists in the detection of the presence of genetic material of the virus or bacteria using techniques based on the PCR method. Couples who have problems conceiving a child are advised to carry out genetic tests for the following infections: Chlamydia trachomatis (chlamydiosis), Neisseria gonorrhoeae (gonorrhea), Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma parvum / Ureaplasma urealyticum, Trichomanas vaginalis, Treponema pallidum (syphilis). Curing chronic bacterial infections of the genitourinary system should  be preceded beforing trying for a baby.


When nothing is found – what next?


In case of infertility and normal results for the above-mentioned genetic tests, you should go to the infertility treatment clinic, where you will get the help of clinical genetics to extend further genetic diagnostics. There are many genetic diseases and syndromes in which infertility may occur (e.g. premature ovarian failure (POF), hypogonadotropic hypogonadism, etc.) and only specialized genetic testing can help explain the genetic causes of these disorders in a particular patient.

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