CHROMOSOMAL
DISORDERS

DNA

The story of DNA

Human genetic information is recorded in the chemical structure of deoxyribonucleic acid (DNA). DNA is stored in cell nucleus structures in the form of chromosomes. The nucleus of a healthy human cell contains 46 chromosomes organised in pairs (23 from the father and 23 from the mother). For the purpose of simpler identification, the individual chromosome pairs are numbered from 1 to 22. The last pair is represented by sex chromosomes, which are referred to as X and Y. If a particular pair consists of two X chromosomes, the person is female; if X any Y are present, the person is male. 

For the purpose of sexual reproduction, our body is able to form a special cell – a reproductive cell (an egg or a sperm), which contains exactly one half of the 46 chromosomes, i.e. 23 chromosomes. After the union of an egg and a sperm, the combination of 23 maternal and 23 paternal chromosomes gives rise to an embryo, which has 46 chromosomes again. Daughter cells formed by its division will contain the same number of chromosomes.

Trisomy – a random error in cell division


Trisomy is not an inherited genetic disorder indicated by family history. In fact, it is always a completely new abnormality caused by improper egg maturation. The risk of trisomy increases with the age of the mother. The most well-known type is trisomy 21, referred to as Down syndrome. Much less frequent forms include trisomy 18 (Edwards syndrome) and trisomy 13 (Patau syndrome).

Abnormalities in the number of sex chromosomes (X and Y) are also frequent. The risk of their occurrence can be screened using TRISOMY test XY.

Abnormalities in the number of chromosomes are caused by random errors in cell division brought by rapid development and intense cell division in the early phases upon fertilisation. In some cases, an extra copy of a chromosome is created, which means there are three instances of a particular chromosome instead of the normal two. This phenomenon is called trisomy – an abnormality that has an extremely serious impact on the further development of the unborn baby.

 

The risk of having a baby with Down syndrome depending on the age of the mother:
Age at childbirth30 years of age40 years of age50 years of age
Risk ratio1 : 10001 : 1001 : 10

TRISOMY test

Down syndrome — trisomy 21

Down syndrome is caused by trisomy 21 – a disorder resulting from the presence of an extra chromosome 21.

Only two thirds of Down syndrome pregnancies will end in a normal childbirth. Approximately 30 % of the pregnancies will end in miscarriage.

This disorder has a serious impact not only on the baby’s overall growth and well-being, but also the shape of its body. It is characterized by distinct facial features and different levels of psychological and mental dysfunction. The most frequent complications include immune and circulatory disorders or gastrointestinal disturbances. Children suffering from trisomy 21 require special health care depending on the extent of their disability. In some cases, Down syndrome symptoms can be moderate and the patient is able to enjoy a relatively long life.

Edwards syndrome — trisomy  18

Edwards syndrome occurs as a result of an extra chromosome 18. The consequences of this chromosome abnormality are serious – the baby is born with low birth weight, an abnormally shaped head, a small jaw, a small mouth, frequently with a cleft lip or cleft palate. In addition to suffering from breathing and feeding problems, the baby is also prone to develop heart diseases. The prognosis is very unfavourable.

Edwards syndrome pregnancies are accompanied by a high risk of miscarriage and a majority of live-born children do not live beyond one year.

Patau syndrome — trisomy  13

The trisomy of chromosome 13 is called Patau syndrome. Trisomy 13 is a serious genetic disorder which can affect all organs, including the brain, heart and kidneys. These children are sometimes born with a cleft palate or deformed limbs. Individuals suffering from this congenital disorder have a very small chance of survival.

Patau syndrome pregnancies are characterized by a high risk of miscarriage or still-born babies.

TRISOMY test XY

TURNER SYNDROME 45,X

In laboratory terms, Turner syndrome corresponds to karyotype 45,X, which means that one sex chromosome is missing from the standard set and there is only one X chromosome remaining in the complement. The cell line with the missing X chromosome may have a mosaic form and the resulting clinical symptoms may be less severe. Turner syndrome has an incidence ratio of 1 out of 2,500 girls born. When untreated, developed clinical cases are characterised by short stature (at the time of birth or at a very young age) and underdeveloped secondary sexual characteristics, including amenorrhoea and infertility. Partially treatable using hormonal substitution, the impaired stature and sex characteristics in patients with Turner syndrome have been treated increasingly successfully in the recent years. Although infertility associated with Turner syndrome can be treated using advanced assisted reproduction methods, successes on this front have been rare so far.

Several other symptoms either disappear with time or, if adequately treated, disappear (e.g. lymphedema) or become less severe (e.g. pterygium and shield-shaped chests). Turner syndrome characteristics also include congenital kidney defects and congenital heart defects (CHDs). Severe CHDs can have a negative impact on treatment in particular.

KLINEFELTER SYNDROME XXY

In laboratory terms, Klinefelter syndrome corresponds to karyotype 47,XXY, which means that the standard chromosome set with a male complement of XY contains at least one extra X chromosome. The cell line with an extra X chromosome may have a mosaic form and the resulting clinical symptoms may be less severe; however, if there several extra X chromosomes are present, the clinical symptoms can be more developed.  Klinefelter syndrome has an incidence ratio of 1 out of 500 boys born. When untreated, developed clinical cases are characterised by greater height accompanied by underexpressed female secondary sexual characteristics (gynaecomastia, gynoid obesity), incomplete puberty, and infertility. Generally more subdued and sensitive, patients frequently develop speech and learning defects. Their genitals are small or characterised by undescended testicles and a smaller penis; patients are more likely to suffer from hypospadias. As opposed to other men, patients with Klinefelter syndrome run a high risk of developing diseases determined by the XX sex chromosome complement, such as breast cancer. Their low testosterone, incomplete puberty, and underdeveloped sexual characteristics are partially treatable using hormonal substitution. Although infertility associated with this syndrome can be treated using advanced assisted reproduction methods, successes on this front have been rare so far.

Current guidelines mostly recommend that the mother-to-be should not be told about running a risk of Turner or Klinefelter syndromes; they also recommend that the patient should not be referred for an invasive verification method (e.g. amniocentesis). Respecting these recommendations, our TRISOMY test results contain information about the most likely sex of the unborn baby but no details of any sex chromosome number abnormalities even if they are found in the course of our analysis. Before she undergoes a TRISOMY test + screening, the mother-to-be needs to decide, in the light of all general indication criteria, whether she wishes to know the chromosome-based sex of her unborn baby. If she does, she also has to decide whether she wants to know about potential findings related to syndromes 45,X and 47,XXY, which are responsible for Turner and Klinefelter syndromes, respectively. Compared to autosome aberrations (chromosome 21, 18, and 13 trisomy in particular), there has been a drop in the number of requests for an abortion when sex chromosome aberrations (45,X and 47,XXY) are detected as part of prenatal genetic diagnostics. For this reason, we respect the current guidelines that recommend informing the patient about potential risks or results of differential diagnostics in the postnatal period. This information is provided on condition that the mother-to-be wishes to be told and her treating doctor grants her request.

XYY syndrome and XXX syndrome

XYY syndrome affects men with karyotype 47,XYY. The cell line with an extra Y chromosome may have a mosaic form. The syndrome occurs with an incidence ratio of 1 out of 1 000 boys born. The clinical symptoms are inconspicuous: XYY men are usually characterised by an above-average height and physiological sexual development. In early childhood, XYY syndrome is associated with light disorders (speech development, learning, motor activity, and emotional difficulties, as well as some of the symptoms in what is called the autistic spectrum).

XYY syndrome affects women with karyotype 47,XXX. The cell line with an extra X chromosome may have a mosaic form, frequently with a monosomy X share. The syndrome occurs with an incidence ratio of 1 out of 1 000 girls born. The clinical symptoms are inconspicuous: XXX women are usually characterised by an above-average height and physiological sexual development. In early childhood, XXX syndrome is associated with light disorders (speech development, learning, motor activity, and emotional difficulties) and congenital kidney disorders are more frequent, too.

Current guidelines mostly recommend that the mother-to-be should not be told about XYY or XXX syndrome risks; they also recommend that the patient should not be referred for an invasive verification method (e.g. amniocentesis). Respecting these recommendations, our TRISOMY test results contain information about the most likely sex of the unborn baby but no details of any sex chromosome number abnormalities even if they are found in the course of our analysis. Before she undergoes a TRISOMY test + screening, the mother-to-be needs to decide, in the light of all general indication criteria, whether she wishes to know the chromosome-based sex of her unborn baby. If she does, she also has to decide whether she wants to know about potential findings related to syndromes XYY and XXX, or only those related to syndromes  45,X and 47,XXY, which are responsible for Turner and Klinefelter syndromes, respectively (along with the limitations specified above).

TRISOMY test +

MICRODELETION SYNDROMES

Due to biological and technological limitations, the accuracy of our microdeletion syndrome examination is relatively lower compared to trisomy 21, 18, and 13. Given the generally low occurrence of microdeletions in the population, there have been no studies that would reliably validate the accuracy of our test targeting these syndromes.

Syndrome name    Localisation   Incidence                              Deletion scope      
DiGeorgeov syndrome 22q11 1 : 4000 3 – 5 Mb
Microdeletion syndrome 1p36 1 : 5000 – 10 000 1 – 10 Mb
Prader-Willi syndrome and Angelman syndrome 15q11 1 : 10 000 – 30 000 2 – 9 Mb
Cri-du-chat syndrome 5p15 1 : 20 000 – 50 000 5 – 35 Mb
Wolfov-Hirschhornov syndrome 4p16 1 : 50 000 2,5 – 3

 

22q11 DIGEORGE SYNDROME 

The most frequent microdeletion syndrome, DiGeorge syndrome causes a severe disorder that can manifest in any system or any part of the human body. The symptoms can be treated only in some cases. The disorder is characterised by congenital heart defects (CHDs), immune system disorders, kidney defects, and cleft palate issues, frequently combined with severe mental retardation. The symptoms vary considerably. In some cases (especially those involving less pronounced symptoms), familial transmission and intrafamilial variability can be assumed.

Since CHDs may actually be the only symptom of 22q11 deletion, the syndrome is frequently indicated by prenatal genetic examinations when a congenital hear disorder is detected or when such a disorder is indicated by ultrasound screening.

1p36 DELETION SYNDROME

Similarly to DiGoerge syndrome, 1p36 deletion syndrome is one of the most frequent microdeletion syndromes. It leads to an extremely severe and untreatable disorder characterised by very heterogeneous symptoms. Its main characteristics include mental retardation combined with behavioural disturbances, growth delays, and hypotonia.

15q11 PRADER-WILLI SYNDROME & ANGELMAN SYNDROME

Although they are different from one another in terms of their clinical symptoms, both syndromes are caused by an absence or dysfunction of gene functions in one and the same critical region of chromosome 15. Although most cases are caused by a deletion affecting a critical region of chromosome 15, other cases can be caused by sporadic mutation, methylation disorders, or uniparental disomy rather than deletion. Under the circumstances, it cannot be expected that microdeletion screening will detect all actual Prader-Willi and Angelman syndrome cases.

Prader-Willi syndrome is characterised by hypotonia, poor sucking reflexes, feeding difficulties in early infancy, followed by hyperphagia and obesity from age 2 onwards. Mental retardation is relatively mild, but various other behavioural disorders are present in addition to excessive eating.

Angelman syndrome characteristics are less expressed. Usually not obvious at birth, the clinical symptoms start developing around the age of 12 months. They include psychomotor activity and speech development delays. The patient’s medium mental retardation is accompanied by progressively pronounced behavioural disturbances.

5p15 CRI-DU-CHAT SYNDROME 

Cri-du-chat syndrome is an older, cytogenetically defined syndrome (also known as Lejeune syndrome or 5p- syndrome) because more extensive deletions could already be detected using optical microscopes in the era of traditional cytogenetics.

The name “cri-du-chat” (cat’s cry) comes from the leading clinical symptom this syndrome is characterised by in the period of early infancy. Combined with characteristic facial dysmorphia, the symptom is a distinguishing feature of this syndrome in comparison to other disorders involving growth delays, psychomotor retardation, microcephaly, and hypotonia. The scope of actual deletion correlates with the severity of the patient’s disability.

4p16 WOLF-HIRSCHHORN SYNDROME

Wolf-Hirschhorn syndrome (also known as 4p- syndrome) belongs to the same group of syndromes identified by traditional cytogenetics. The severity of its clinical symptoms correlates with the actual scope of deletion. Similarly to cri-du-chat syndrome, this syndrome comes with characteristic facial dysmorphia combined with microcephaly, hypertelorism, protruding eyes, and a short philtrum. Severe growth and psychomotor retardation is accompanied by other serious symptoms, such as hypotonia, epileptic fits, and congenital development defects affecting internal organs (esp. heart and kidney defects).

 

Diagnosing chromosomal abnormalities

During her pregnancy, every mom-to-be undergoes a number of preventive examinations focused on her unborn baby’s health as well as her own. Several screening tests performed during this period target developmental abnormalities.

1. Biochemical prenatal screening

Biochemical prenatal screening determines the risk of Down syndrome (trisomy 21) and Edwards syndrome (trisomy 18), as well as the risk of open neural tube defects or anterior abdominal wall defects.
The risk ratio is determined in relation to the age of the mother and on the basis of specific biochemical or ultrasound parameters.

These parameters are defined in both the 1st and 2nd trimesters.

In the 1st trimester, the plasma protein A (PAPP-A) and the free beta subunit of human chorionic gonadotropin are determined on the basis of biochemical parameters. The most important value measured using ultrasound is NT (nuchal translucency). The measuring itself must be performed by an experienced certified sonographer and requires adequate equipment.

In the 2nd trimester, alpha fetoprotein (AFP), human chorionic gonadotropin (HCG), and unconjugated estriol (uE3) are determined.

Depending on the screening parameters used, we distinguish the following test types:

  • a combined test (only 1st trimester biochemical parameters + NT),
  • a triple test (only 2nd trimester biochemical parameters),
  • a serum integrated test (1st and 2nd trimester biochemical parameters, joint evaluation upon the 2nd trimester blood test),
  • an integrated test (1st and 2nd trimester biochemical parameters + NT, joint evaluation upon the 2nd trimester blood test).

Depending on the test type used, it is possible to identify as many as 70-90 % of Down syndrome foetuses. In practice, however, positive results, i.e. having an increased risk of chromosomal abnormality, can be wrong in 3 – 7 % of all cases (false positive results).

Pregnant women with a positive screening result should subsequently undergo more demanding specific tests, such as amniocentesis, chorionic villus sampling, echocardiography, etc. These tests should confirm or exclude the risk of the presumed foetal disability.

A screen-positive result does not mean that your baby has a disability. It only means the risk is higher and further tests are necessary to exclude or confirm the disability.

2. Ultrasound

Ultrasound is an important type of examination in pregnancy. In the period between the late first and early second trimesters, a nuchal translucency ultrasound examination is performed to measure the thickness of the nuchal fold. This test can reveal whether your baby is likely to have Down syndrome. In this period, the morphology of the foetus is examined to exclude serious developmental disorders. This type of diagnostics must be performed by a skilled specialist and requires adequate equipment.

3. Amniocentesis

Amniocentesis is a procedure which involves taking a sample of amniotic fluid directly from the uterus. In the early stages of pregnancy, chorionic villus sampling is sometimes used as a diagnostic alternative (it involves examining the foetal portion of the placenta). Both are invasive surgical procedures performed by guiding a needle through the belly into the uterus.

Samples are analysed using genetic laboratory techniques. Prior to the microscopic examination of the chromosome number and other parameters, the isolated foetal cells are cultured under laboratory conditions. The result is called a “karyotype” and it’s used to evaluate all 23 pairs of chromosomes.