General information on genetics
In each of our cells there exists a nucleus which contains the different chromosomes. These chromosomes are long chains consisting of hereditary material (DNA).
Chromosomes can be classified according to size and form, and numbered of large to small. These classified chromosomes form a karyotype. In each cell we have 2 copies of each chromosome, of which one originates from our father and one from our mother. So there are 23 chromosome pairs, and the total sum of chromosomes is 46. In the germline (egg from the woman and sperm from the man), however, there are 23 chromosomes, and only one copy of each chromosome pairs is present. When the 23 chromosomes from the egg meet with the 23 chromosomes from sperm cell, a fertilised egg or zygote with 46 chromosomes arises. From this zygote the child will develop. 44 of the 46 chromosomes (22 pairs) are present in both women and men : these chromosomes called autosomes. The remaining 2 chromosomes are called sex chromosomes. There are 2 sort of sex chromosomes : the X and the Y chromosome.
A woman has two X-chromosomes and no Y chromosome, because she gets an X chromosome from both her father and her mother. A man has two different sex chromosomes: an X chromosome that he inherits from his, and a Y chromosome which comes from its father. A man can make therefore both sperm cells warrants with an X chromosome, and an Y chromosome. A woman has only eggs with an X chromosome. If a sperm cell fertilising the egg (which always contain an X chromosome) contains an Y chromosome the resulting child will be a boy (XY). If a sperm cell contains an X chromosome, a girl (XX) will develop.
Because we have 2 copies of each autosome, we have 2 copies of each autosomal genes. Genes which lie on the X chromosome have 1 copy in a man and 2 in a woman. Genes on the Y chromosome are present in 1 copy in men, whereas women do not have these genes.
Our hereditary material is made of a chemical substance called Deoxy Nucleic Acid (abbreviated: DNA).
This DNA actually is a long chain of four different nucleotides: adenine (A), cytosine (C), guanine (G) and thymine (T). The DNA chain is very long and contains approximately 3 billion of these nucleotides. The DNA chain is made out of 46 different DNA chains, which are called chromosomes. These chromosomes harbour all the different genes, which is a separate unit of DNA with a specific function. Humans has approximately 25,000 genes. Most of these genes are responsible for the production of a specific protein. Changes in DNA are called mutations. These mutations can be the cause of hereditary diseases.
The chromosomes exist from separate units of DNA called genes, which all have their own function. We have approximately 25,000 genes in each cell. Most of these genes have been discovered during the Human Genome Project, a very important scientific project in which research workers from the all over the world took part in order to decipher the DNA code. A large part of this project has already been completed, and most of our genes have been identified. Geneticists are now trying to elucidate the function of all these genes. Most genes encode one or more specific proteins, and each of these proteins has its own function in cell. These proteins determine all our characteristics, such as how we look (the colour of our eyes, etc), but also all genetic diseases.
Down syndrome or trisomy 21
The most well-known example of a chromosome anomaly is Down syndrome. In 1866 Doctor Langdon Down described this chromosome anomaly for the first time in the medical literature. In genetics, and in medicine in general, it is quite common to call diseases after the doctor that described them for the first time.
A syndrome is a disease with anomalies of several organs, such as the eyes, brain and the heart. Many syndromes are due to a genetic anomaly.
Down syndrome is caused by an extra (third) chromosome 21. These individuals have therefore not 46, but 47 chromosomes. Whereas everyone has two chromosomes 21, they have 3. Therefore, Down syndrome is also called trisomy 21. The trisomy is usually due to an abnormality of the egg of the mother: normally all reproductive cells (eggs and sperms) carry only 23 chromosomes (one of each). At fertilisation the 23 chromosomes from the female egg than join the 23 chromosomes from the male sperm to form a fertilised egg or zygote with the normal 46 chromosomes. When one of the reproductive cells has an extra chromosome 21, the fertilised egg has 47 chromosomes with 3 chromosomes 21, resulting in Down syndrome.
With the age of the mother, particularly from 36 year on, increases the risk that the egg contains 2 instead of 1 chromosome 21. Therefore, also the risk on a child with Down syndrome steadily increases with maternal age. For this reason pregnant woman with a certain age (frequently from the age of 36 years) have prenatal tests to exclude Down syndrome. An average couple has risk of approximately 1 on 200 on a child with a chromosome anomaly, and 1 on 600 for trisomy 21.
Edwards syndrome or trisomy 18
Also trisomy 18 or Edwards syndrome is a serious syndrome where the babies generally die in the first life year. The babies have malformations of many organs.
Patau syndrome or trisomy 13
Trisomy 13 is a very severe chromosome anomaly with early death. Trisomy 13 babies frequently have cleft lip and palate, and congenital heart malformations.
Turner syndrome or monosomy X
Girls with Turner syndrome have 1 instead of 2 X chromosomes (monosomy X). They are small, have no menstruation and are infertile. Frequently also there exists a broad neck (webbed neck). The intellectual development is normal or slightly behind.
Klinefelter syndrome is caused by an extra copy of the X chromosome (XXY). It only affects boys. that may have speech delays and other learning disabilities and tend to be taller than average, but otherwise have few physical anomalies. Men with Klinefelter syndrome are usually infertile and often benefit from hormone treatment starting at puberty.
Ultrasound uses ultrasonic waves to make a picture of the fetus. The echo apparatus sends out sound waves to the body of mother and child, and catches the echos (hence the denomination echography) of these sound waves. These echos are then converted into a picture of the fetus. Ultrasound is very frequently used in medicine to visualise internal structures, just like CT scan and MRI. The ultrasonic sound waves are harmless for mother and fetus.
With ultrasound it is possible to visualise structural anomalies of the fetus such as growth retardation, neural tube defects (spina bifida), hydrocephalus, heart malformations, etc. Because ultrasound only visualises the form and not the function, ultrasound cannot exclude functional defects (eg mental retardation, epilepsy, etc). A fetal ultrasound to visualise the fetus and its organs is called a structural fetal ultrasound; it is best performed around week 18-19 of gestation. Ultrasound is the most important prenatal screening test, and should therefore be performed in each pregnancy, certainly when there is an increased risk for a child with a congenital or genetic anomaly. This is the case if there is (was) a previous child with such anomaly, or if of the parents themselves have such an anomaly. Some malformations can be visualised already very early in pregnancy (from week 12 on).
With an amniocentesis approximately 10-20 ml amniotic fluid is absorbed with a needle introduced into the amniotic cavity through the abdomen. Amniocentesis causes little discomfort or pain for mother and foetus (to compare with an injection of medicines). The procedure has only a small risk for the pregnancy. In approximately 1 on 200 cases (0,5%) miscarriage results because of haemorrhage, infection or leaking of amniotic fluid after the puncture. Of course, not every miscarriage after an amniocentesis is the consequence of this test, because also women without amniocentesis can have a miscarriage. The risk of touching the fetus with the needle is very small.
An amniocentesis is performed to obtain amniotic fluid and foetal cells that float in the amniotic fluid. These cells are fetal cells from the skin and internal membranes of the fetus. Both amniotic fluid and amniotic cells can be used for prenatal testing.
Tests that can be performed are cytogenetic analysis, molecular tests, metabolic tests and determination of alpha-foetoproteine (AFP). Usually specific genetic tests are performed to exclude specific syndromes for which there exists an increased risk. Whatever the indication for the amniocentesis cytogenetic or array CGH analysis (to exclude Down syndrome and other chromosome anomalies), and AFP determination (to exclude a neural tube defect) are performed. Sometimes a rapid screening chromosome analysis is performed to exclude some frequent chromosome disorders such as Down syndrome, trisomy 13 and trisomy 18 (this test is called the fast FISH test or QF-PCR test). In some countries also cystic fibrosis is screened for routinely.
The most frequent indication for amniocentesis used to be a slightly increased risk (1-5%) for cytogenetic anomalies based upon an abnormal Triple test or combination test, although many women now prefer NIPT as it is non-invasive. Amniocentesis is carried out preferentially between week 15-16. The result of the AFP tests and the fast FISH test or QF-PCR test are already ready after 3 days. Additional tests (complete cytogenetic test, molecular and biochemical tests) usually take longer (2-4 weeks).
When an anomaly is detected, the parents have to discuss the consequences of this anomaly with the clinical geneticist. At this time the pregnancy is already advanced (16-18 weeks). When the parents decide to terminate the pregnancy because of the seriousness of the fetal anomalies, this is not possible anymore by suction curettage, but is performed by induction of (premature) labor with drugs.
Chorionic villi sampling (Chorion biopsy or CVS)
During chorionic villi sampling a needle is introduced through the abdominal wall or vagina/cervix into in the placenta, and a number of chorionic villi are absorbed. These villi contain fetal cells that can be studied in the laboratory. The risk of a miscarriage due to the CVS varies between 1 and 2%, and is slightly higher than that of amniocentesis because CVS is performed earlier (week 11), and the foetus is more sensitive for an intervention then in the 16th week when amniocentesis generally is performed.
Tests that can be performed after CVS are cytogenetic analysis, molecular tests, metabolic tests. Only alpha-foetoproteine (AFP) cannot be tested as it is not present in chorionic villi. But CVS has also some advantages compared to amniocentesis. CVS is preferred test for molecular tests because chorionic villi contain more DNA than amniotic fluid. The most important advantage of CVS is that it can be performed a month earlier than amniocentesis (11th versus 16th week). The result of the CVS test is usually available in week 12-13, whereas the result of the amniocentesis is only ready in week 17-19. When the parents decide to terminate the pregnancy because of the seriousness of the fetal anomalies, this usually can be performed by suction curettage after CVS, which is less stressful than induction of (premature) labour with drugs after amniocentesis.
Second trimester maternal screening (Triple test)
The triple test is a screening test with determination of biochemical parameters in blood of the mother sampled between week 14-18 (hence: second trimester test) in order to estimate the risk on Down syndrome.
The AFP level in maternal blood is on average lower than in normal pregnancies. For that reason the determination of AFP in maternal blood is a screening test for Down syndrome. The test becomes more reliable when combined with the determination of other proteins in maternal blood, including HCG (Human Chorionic Gonadotrophin), and free oestradiol. Therefore this test is called the triple test. This test is not a real diagnostic test for Down syndrome, but a screening test which only indicates an increased risk for Down syndrome. Most of the women (more than 95%) with an abnormal triple test (risk above 1 on 300) have a normal baby without Down syndrome or chromosome anomaly.
On the other hand some women with a normal triple test can have a child with Down syndrome or other chromosome anomaly. Therefore, a normal triple test is not a guarantee for a healthy child.
First trimester maternal screening (Combination test)
Since 2000 maternal Down syndrome screening in the second trimester of the pregnancy has been replaced by first trimester screening in some Western countries. The first trimester Down screening combines biochemical parameters in maternal blood with ultrasound parameters of the foetus. The biochemical tests are Papp-A (Pregnancy Associated placental protein-A) and free beta-HCG (Human Chorionic Gonadotrophin). These values are combined with ultrasound measurements of the nuchal translucency (NT), a translucent spot in the neck of the fetus and crown-rump length (CRL) of the fetus.
The ultrasound should be performed between weeks 11-13. The blood parameters can be performed at the same moment, but better between weeks 9-10 because the results of the biochemical test are then ready at the time of the ultrasound a few weeks later so that the measurements can be combined and the pregnant woman given the final risk assessment.
Just like the triple test the 1st trimester Down screening is not a diagnostic test, but a screening test which only indicates the risk for Down syndrome.
NIPT is the newest prenatal test offered as an alternative for amniocentesis, and Down syndrome screening with the Triple or Combination test. Extended info is available in our NIPT information brochure.