Genetics

In the past decade the assisted reproductive techniques (ART) and the development of genetics made it possible to discover the causes of genetic origin infertility. While earlier these kinds of patients who visited IVF (in vitro fertility) centres could not have babies because they had genetic problems causing their infertility, nowadays with the help of modern ART (e.g. ICSI – intracytoplasmatic sperm injection) they can have genetically their own offsprings. Although these revolutionary infertility treatment methods make it possible to inherit genetic defects leading to infertility hereby increasing the rate of genetic origin infertility in future generations. Knowing the results, we can estimate the risk of passing the couple's own genetic features or possible defects onto the offspring with different assisted reproductive techniques. The families taking part in the infertility examinations will undergo a genetic consultation where after getting enough information they can decide upon which genetic examination or assisted reproductive technique to choose.


I. Genetic examinations prior to the assisted reproductive technique

1. Cytogenetic examination (chromosome-examination)

After taking a detailed family anamnesis, a cytogenetic examination is recommended for the couple in the following cases:

1.1. Female origin infertility

  • In cases of primer/secunder oligoamenorrhoea, cytogenetic examination is necessary, if there has no other cause risen during the gynaecologic and endocrinologic examinations.
  • Premature ovarian failure (POF) is such a state which occurred before the age of 40 and is characterized by amenorrhoea, hypoestrogenism, increased gonadotropin-level and infertility. The 4–18% of secunder amenorrhoeic patients suffers from early ovarian exhaustion.
  • Habitual miscarriage. Two or more spontaneous miscarriages within the first 8–10 gestational weeks suggest structural chromosome disorders (translocations, inversions). These are such genetic deviations which do not cause a problem for the couple but lead to miscarriage of pregnancy even in 20–30%.


1.2. Andrologic origin infertility

In case of andrologic origin infertility 5% of the causes are chromosomal which rate increases to 15% in case of azoospermia.

  • Numeral differences in sex chromosomes. The most common cause of serious oligospermia/azoospermia is the Klinefelter-syndrome (47, XXY), where compared to a normal male caryotype (46, XY) there is an extra X-chromosome. Other differences in sex chromosome numbers greatly decrease fertility.
  • Structural deviation of Y-chromosome. In 10–15% of men who suffer from serious oligospermia/azoospermia there is a bit missing from the Y-chromosome (deletion). This is the "azoospermia factor" (AZF) region.
  • Structural deviation of autosomes. Translocations and inversions on non-sex chromosomes often cause spontaneous miscarriage.


2. Defining gene-mutations leading to infertility.

It is known that any slight change in human DNA structure can lead to a disease. The following gene-mutation examinations might be needed during the infertility examinations:

2.1. Female origin infertility

  • Fragilis X-syndrome. The FMR1 gene on the X-chromosome is responsible for the pathological amplification of a DNS section ("fragility"). If the length of the pathological base-pair is longer than 200 base-pairs ("full mutation"), then due to the dynamic mutation, mental retardation which is bound to X will occur in males. If the length of the pathological base-pairs is between 60 and 200 ("premutation"), then premature ovarian failure (POF) will occur in 10–15% of otherwise healthy females causing infertility to them.
  • Other gene-mutations. These are such rare mutations which occur on genes coding hormones or their receptors (e.g. Kallman-syndrome, androgen receptor insensibility syndrome).


2.2. Andrologic origin infertility

  • Cystic fibrosis (CF) is one of the most common autosomal diseases which are inherited recessively. Every 25th human carries a mutation necessary for its developing. It is caused by the mutation of the CFTR gene coding the cystic fibrosis transmembrane regulator protein which controls iontransport through the cell-membranes. The infertility of males suffering from cystic fibrosis (they have two mutant genes) is caused by the atrophy or lack of vas deferens which let flow the sperms from the testicles. Certain CFTR mutations also cause the lack of vas deferens in the carrier males who do not show symptoms of CF (congenital aplasia of the vas deferens- CAVD). 5% of azoospermial males belong into this group.
  • Other gene-mutations These are such rare mutations which occur on genes coding hormones or their receptors (e.g. Kallman-syndrome, androgen receptor insensibility syndrome).


II. Genetic examinations during the assisted reproductive techniques

Preimplantation genetic diagnosis (PGD)

With this method we can carry out genetic tests on one single cell of the six-to-eight cell-group (pre)embryo which was conceived during the IVF, before transferring it into the uterus. On the 3rd day after the fertility (stage 6–8 cells) one or two cells can be extracted from the preembryo so that its development is not endangered. From the extracted cells we can find out which preembryos are affected by genetic diseases with the help of fluorescent in situ hybridisation (FISH) or molecular genetic examination (polymerase chain reaction – PCR) and only the healthy embryos are transferred back into the uterus. Due to this method – opposed to the traditional prenatal diagnostics (placenta biopsy, amniocentesis) – with using PGD, there is no need to think about a possible abortion if the foetus might turn out to be ill. The number and structural disorders of chromosomes can be examined with the help of PGD, (e.g. Down-syndrome, translocations) or genemutations in case of monogene diseases (e.g. cystic fibrosis, muscle atrophy, Huntington-disease, haemophilia). The deletions on the Y-chromosome that lead to azoospermia can be examined, which will be inherited by male babies if ICSI method is used. We can find out about the sex of the foetus and the numbers of chromosomes (preimplantation genetic diagnosis for aneuploidy screening – PGD-AS). This is really significant for mothers above the age of 35 because we can avoid transferring back embryos with aneuploid (differing in number from the normal 46) chromosomes which occurs more frequently as mothers grow older. This way the number of fetal chromosome disorders can be reduced and the success of assisted reproduction can be increased and the number of spontaneous miscarriage decreases also. (It is known that unsuccessful implantation and early spontaneous miscarriage happens due to fetal chromosome abnormalities in vast majority of the cases.) The licensing process of PGD technique is in progress at the moment in our institute.


III. Genetic examinations after the assisted reproductive techniques
The frequency of fetal diseases/development abnormalities in pregnancies conceived by IVF does not differ from the numbers in spontaneous pregnancies according to different studies if the comparison was done on basis of a proper control group (mothers' age, parity, single- or twin-pregnancy). Though we have to expect the possible transfer of maternal or paternal origin genetic problems in pregnancies helped by assisted reproductive techniques, and also count on quite frequent multiple-pregnancies, that are why high quality prenatal diagnostics is a very important part of a modern IVF centre.

Prenatal diagnostics

Prenatal diagnostics is a part of clinical genetics which includes all the methods and proceedings that help to get information about the health of the foetus or embryo. By the help of the methods we can find those fetal abnormalities which require an intrauterine or early neonatal treatment or in incurable cases make abortion necessary. Prenatal diagnostics makes it possible to prevent the birth of an ill baby and even those families can take on a pregnancy under the protection of prenatal diagnostics who would not do so because their risk is higher than average. All the opportunities provided by modern fetal diagnostics are available at the Versys Clinics.

1. Genetic Consultation

The separate screenings and diagnostic examinations are united by the Genetic Consultation. Within this, the data from the anamnesis are discussed, the results are evaluated, detailed information is provided and the couple makes those decisions which are needed for the pregnancy. After taking into consideration the results of the ultrasound examination and the biochemical tests, considering the possible risk factors deriving from the mother's age or the genetic status before IVF, the individual risk is measured for the pregnancy at this Genetic Consultation.

2. Techniques applied to visualise the foetus (ultrasound, fetal echocardiographia)

A specialist with the highest "C" type of qualification can do ultrasound examination which shows or excludes the different structural anomalies of the foetus. The examination is used to judge the seriousness of fetal deviances and to make a realistic recommendation for a possible invasive diagnostic action if necessary (1. trimester: embryosonographia, nuchal translucency-measurement; 2. trimester: "genetic ultrasound examination", fetal echocardiographia).


3. Biochemical tests from mother's blood to check chromosome abnormalities

  • Combined tests in the 1st trimester: Blood sampling from mother (PAPP–A and free beta–hCG) in the 10–13th gestational week and ultrasound examination (NT measuring + CRL-measuring) in the 11–13th week of pregnancy.
  • Tests in the 2nd trimester: Triple or quadruple test. Blood sampling from mother in the 16–17th gestational week (AFP, free beta–hCG, free ostriol and the previous ones + inhibin–A) and genetic ultrasound examination in the 18–19th week.
  • Integrated tests in the 1st and 2nd trimester: From the Down-test results from the 1st and 2nd trimester the risk of Down-syndrome is calculated jointly. The procedure of the test is the following: in the 1st trimester blood sampling for PAPP–A, and NT-measurement by ultrasound examination, and then in the 16th gestational week repeated blood sampling for AFP, free beta hCG, free ostriol and inhibin–A.


The discussion of blood sampling and ultrasound examination results and information about possible further genetic examinations is held at the Versys Clinics, at the Genetic Consultation.

4. Fetal tissue sampling (amniocentesis, chorionbiopsia)

With regard to the fact that the procedures are risky they cannot be made compulsory so after giving proper information about them, always the couple decides if they undertake them or not during the Genetic Consultation. It is also up to the couple to decide about the fate of the pregnancy if one of the examination methods shows an illness (developmental abnormality) of the intrauterine foetus.

  • Genetic amniocentesis (GAC): Through the mother's abdominal wall amniotic fluid is taken by a thin needle with ultrasound monitoring to find or exclude the disease of the intrauterine foetus mainly in the 16–20th gestational weeks.
  • Chorionic villus sampling, CVS) It means a sampling from the placenta with ultrasound monitoring. The chorionic tissue is suitable for defining the fetal chromosome composition and to examine enzymes and to do DNA-level fetal diagnostics. It can be carried out from the 10th gestational week until terminus.


5. Reduction of multiple pregnancies. If fetal abnormalities are found in multiple pregnancies there is a chance for selective pregnancy termination.

 

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