Medical genetics

Examination in preparation for conception, examination of infertile couples

The genetic testing of the couple should begin before the attempts for conception. The aim of the genetic consultation is to detect diseases with an inherited component, which can reappear in individual generations according to a genealogical study. At the same time, our goal is to reveal the hidden transmission of predispositions to hereditary diseases.

The geneticist indicates some of the following tests:

• Examination of chromosomes in both partners – in case of a significant disorder of the male partner's spermiogram, we test for the loss of material on the Y chromosome (microdeletion); in women with premature ovarian failure, we test for the fragile X syndrome.
• Examination of thrombophilic mutations in women (congenital predisposition to increased blood clotting).
• Examination via a panel for hidden predispositions to hereditary diseases. The panel for hidden carriers contains a total of 77 genes that are inherited autosomally recessively (see Figure 1). The panel also contains some diseases inherited on the X chromosome (see Figure 2). Serious diseases primarily include cystic fibrosis, spinal muscular atrophy, congenital deafness, the panel contains predispositions to metabolic diseases.
• Examination of the estimated response to hormonal treatment (gene examination).
• According to the results of the examination of the couple, we propose suitable methods of assisted reproduction, we discuss the possibilities of pre-implantation genetic testing (PGT), we recommend monitoring during future pregnancies (prenatal diagnosis).

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Embryo examination (pre-implantation genetic testing)

Genetic testing of embryos can be performed as part of assisted reproduction methods, i.e., before implantation in the uterus (pre-implantation genetic testing = PGT). The method of genetic testing of embryos is based on the conclusions of the genetic consultation. We provide pre-implantation genetic testing:

PGT-A -\– pre-implantation genetic testing of aneuploidies. Examination of embryos to exclude new chromosome defects.

PGT-SR – pre-implantation genetic testing for chromosomal defects.

PGT-M – pre-implantation genetic testing for monogenic hereditary diseases. Examination of germs to rule out hereditary disease, where one or both partners are carriers of disease predisposition.

Examination during pregnancy – prenatal diagnosis

Screening for congenital malformations of the foetus is a simple and affordable examination with the aim to find women at risk of having a foetus with a serious defect. Screening examinations during pregnancy are performed in the following steps:

During the first visit to the prenatal clinic, the mother is informed about the possibility of screening for birth defects. Ultrasound is used to determine the duration of pregnancy. The risk of some genetic defects in offspring increases with increasing age. The risk increases in women over 35 and in men over 45. High-risk couples should consult a medical geneticist who will discuss the most appropriate follow-up procedure.

First part of the screening for birth defects

1) In week 10-11, maternal blood is collected for testing of pregnancy-associated plasma protein A (PAPP-A) and the free beta subunit of chorionic gonatropin (FB-hCG) levels.

2) In week 12-13, ultrasound is used to measure nuchal translucency (NT) and the presence of the nasal bone (NB) of the foetus. If necessary, further ultrasound signs of the foetus are examined (e.g. flows in the vessels of the mother and the foetus).
The risks of congenital defect in the foetus are determined based on the combination of results from blood sampling and ultrasound examination. Women at high and medium risk are consulted by a clinical geneticist.

Second part of screening for birth defects

1) In week 14-17, maternal blood is collected, if the screening in the first part was negative. Alpha-fetoprotein (AFP), chorionic gonadrotropin (total hCG), unconjugated estriol (uE3) are examined.

Subsequently, the risks of congenital malformation are calculated using the values from the first and second part of the screening. At the same time, the ultrasound examination is also used (so-called integration). Women at high and medium risk are consulted by a clinical geneticist.

2) In week 20-22, ultrasound screening of foetal morphology with examination of foetal heart continues.</p>

If the risk of foetal birth defects is found during pregnancy, we offer:

Invasive examination options

• collection of chorionic villi, collection of amniotic fluid

Chorionic villi or amniotic fluid samples are used for QF-PCR of the most common aneuploidies (defects in the number of chromosomes 13, 18, 21, X, Y). The results are available in 48 hours. Furthermore, examination of foetal chromosomes by the array method is performed, providing the results 2-3 weeks after the collection.
 
Non-invasive examination options

• ultrasound examination

Non-invasive tests to detect the most common aneuploidies (defects 13, 18, 21, X and Y) based on the analysis of free DNA from the mother's blood.

Examination of congenital predispositions to blood clots

Increased blood coagulation is influenced by congenital dispositions and external factors (physical activity, smoking, obesity, hormonal contraception, etc.) Individuals with increased blood clotting are at risk of blood clots; blood clots can close blood vessels, cause pulmonary embolism. Blood clots can form in the placenta during pregnancy and jeopardise the course of pregnancy.

We are investigating two significant changes:

Leiden mutation (FV Leiden)

Mutation of the coagulation factor II gene (FII prothrombin)

A significant mutation indicates an innate predisposition to increased blood clotting. If thrombophilic mutations are found, precautionary measures should be taken.

Examination of congenital predispositions to cancer

Examination of congenital predispositions to cancer is performed by a genetic test called CZECANCA (Czech Cancer Panel for Clinical Analysis). This genetic test was developed by a group under doc. MUDr. Kleibl from the 1st Medical Faculty of Charles University and investigates congenital changes of 219 genes associated with cancer. The evaluation of test results mainly focuses on 44 genes that are demonstrably associated with hereditary cancers, such as hereditary breast and ovarian tumours, gastrointestinal tumours, but also a number of other organs (e.g. genes BRCA1, BRCA2, CHEK2, TP53, PALB2, ATM, MLH1, MSH2, MSH6, EPCAM, MUTY H). Congenital changes in other genes in the panel are investigated in the study to find the irregularities in the genetic predisposition of the Czech population to cancer.

CZECANCA uses the next-generation sequencing method (NGS) to examine variants of a number of genes that may be the cause of cancer in one laboratory test.

Indication criteria for the examination of congenital predispositions to cancer:

diagnosis of cancer usually at a young age

• in people with various types of cancer
• in the presence of bilateral tumours in paired organs
• recurrence of the same type of cancer (e.g. breast cancer or colorectal cancer) in the family
• the combination of certain types of tumours in close relatives (breast and ovarian cancer, colon and uterine cancer), especially in cases with cancer at a young age.

The aim of the examination is to identify patients/families with an innate predisposition to certain types of tumours. The results of the examination are ALWAYS communicated to the patient/family during a genetic consultation. At the same time, a report is provided with the oncological risk and suggested preventive measures.

• inclusion in special follow-up programmes from a young age to allow for early diagnosis of possible cancer
• preventive procedures to reduce the risk of disease development
• the treatment of the tumours themselves may need to be adjusted for some types of predispositions
• specification of oncological risk for healthy family members

Genetic counselling for other genetically determined diseases

The geneticist starts the consultation with an initial interview, which includes a detailed assessment of the client's health (personal history). Bring a completed genealogy questionnaire for this consultation. It will be used to create a family tree, the so-called genealogical study. The geneticist recommends further examination after evaluating the data from the patient's personal history and the genealogical study.