Types of genetic abnormality which may lead to haemopoietic malignancy. (a) Point mutation; (b) chromosomal translocation; (c) chromosomal deletion or loss; (d) chromosomal duplication; (e) epigenetic changes: DNA methylation or deacetylation of histone tails suppresses gene transcription.
C, constant region; IgH, immunoglobulin heavy‐ chain gene; J, joining region; V, variable region.
The genetic events in one of the three translocations found in Burkitt lymphoma and B‐cell acute lymphoblastic leukaemia. The oncogene c‐MYC is normally located on the long arm (q) of chromosome 8. In the (8; 14) translocation, c‐ MYC is translocated into close proximity to the immunoglobulin heavy‐chain gene on the long arm of chromosome 14. Part of the heavy‐chain gene (the V region) is reciprocally translocated to chromosome 8.
This is a simplified introduction to chromosomes and chromosome abnormalities. It is to be used only for educational purposes and not for the medical care of an individual. All information should be reviewed with your health care provider. Visit our Library for more chromosome specific information.
Simply put, chromosomes are the structures that hold our genes. Genes are the individual instructions that tell our bodies how to develop and keep our bodies running healthy. In every cell of our body there are 20,000 to 25,000* genes that are located on 46 chromosomes. These 46 chromosomes occur as 23 pairs. We get one of each pair from our mother in the egg, and one of each pair from our father in the sperm. The first 22 pairs are labeled longest to shortest. The last pair are called the sex chromosomes labeled X or Y. Females have two X chromosomes (XX), and males have an X and a Y chromosome (XY). Therefore everyone should have 46 chromosomes in every cell of their body. If a chromosome or piece of a chromosome is missing or duplicated, there are missing or extra genes respectively. When a person has missing or extra information (genes) problems can develop for that individuals health and development.
Each chromosomes has a p and q arm; p (petit) is the short arm and q (next letter in the alphabet) is the long arm. Some of the chromosomes like 13, 14, and 15 have very small p arms. When a karyotype is made (see below) the q arm is always put on the bottom and the p on the top. The arms are separated by a region known as the centromere (red in picture), which is a pinched area of the chromosome. The chromosomes need to be stained in order to see them with a microscope. When stained the chromosomes look like strings with light and dark bands. Each chromosome arm is defined further by numbering the bands, the higher the number, the further that area is from the centromere.
Chromosome disorders are of conditions, caused by constitutional numerical or structural abnormalities of chromosomes.
Normally every cell of the human body has 46 chromosomes, organized in 23 pairs (22 pairs of autosomes, identical in males and females) and one pair of sex chromosomes – XX in females and XY in males. The only exceptions are egg–cells and sperm–cells, which have only haploid set of chromosomes. All normal egg–cells have karyotype 23,X; the sperm–cells may be 23,X and 23,Y. Fertilization of the egg–cell by 23,X–sperm will lead to development of female, fertilization by 23, Y–sperm will produce male organism 46,XY.
Diagnosis of chromosomal disorders requires analysis of chromosomes. Experienced clinicians (geneticists, dysmorphologists) may diagnose many chromosomal disorders by clinical examination. But even if clinical diagnosis is obvious, it has to be confirmed by cytogenetic examination, because almost all chromosomal disorders may exist in different cytogenetic variants with very different prognosis for the family. Therefore, cytogenetic testing is necessary even in patients with a clear clinical diagnosis.
Standard cytogenetic examination requires analysis of chromosomes on the stage of metaphase (metaphase analysis). At this stage of cell division all chromosomes became clearly visible structures. All chromosomes may be recognized by their size, position of a centromere and characteristic pattern of dark and light bands, which can be seen after special staining. A cytogeneticist counts number of chromosomes in each of studied cells and compares its size and banding pattern with a standard. If the studied cells have 46 chromosomes with normal structure karyotype of the person considered as normal. If there are some abnormalities it may be evidence of a chromosomal disorder.
Basically (in normal conditions) all cells of the organism have the same karyotype. Therefore, theoretically all cells may be used for cytogenetic examination. However, the preferential types of cells for chromosomal examination are cells of chorionic villi or amniocytes (in prenatal diagnosis of karyotype) and lymphocytes (for postnatal examination).
Prenatal examination of karyotype is usually performed for several groups of pregnant women. It was shown that pregnancy by a fetus with some chromosomal syndromes (trisomy 21 and trisomy 18) is frequently accompanied by an increase or decrease of several biochemical components of serum. Almost all trisomies (trisomies 13, 18 and 21) occur more often in fetuses of “older” woman (especially after 35 years of age). Age and biochemical parameters (taken together) allow calculation of the risk for Down’s syndrome. If this risk is higher that arbitrarily chosen level (for example, higher than 1%) prenatal examination of karyotype is recommended. Some abnormalities of the fetus, which are noted upon ultrasound examination may be another indication for prenatal cytogenetic diagnosis. The examination may be necessary also for the families where one of the parents is a carrier of a balanced structural chromosomal rearrangement – translocation, inversion, insertion or any complex rearrangement.
There are several ways to obtain cells, identical to fetal cells. The most known test to obtain cells at early stage (~10–11 weeks) is chorionic villus sampling. Under the control of ultrasound the special instrument is inserted via uterine cervix or thorough the abdominal wall. A small piece of placenta with growing chorionic villi is taken for analysis. Short term cultivation is usually needed.
Amniocentesis is a predominant way to obtain cells for prenatal diagnosis. Small amount (5–10 ml) of amniotic fluid is taken from the amniotic cavity via transabdominal amniocentesis. This procedure is usually performed at 14–17 weeks of pregnancy. Amniotic fluid has plenty of amniotic cells. After centrifugation almost all amniotic cells are concentrated at the bottom of the tube. ~1 ml of suspension from the bottom of the tube is placed on the cover slides in the small Petri dishes. A special medium is added to facilitate growth of amniotic cells. After a short-term cultivation (usually 6–7 days) the cells are ready for analysis. A cytogeneticist counts ~20 cells at least from 2 flasks and karyotypes several cells. In some centers the cytogeneticist looks on the cells through the microscope, other centers prefer automatic analysis, when the cytogeneticist looks on the screen of the special computer designed for the selection and analysis of metaphases. There is photographic documentation for every studied person. The results are provided to the patient and (if the results show a chromosomal disorder) the family may decide to continue pregnancy or to terminate it.
Technically amniocentesis may be performed also in a more advanced pregnancy. However amniotic cells obtained after 22 weeks had worse growth potentials (than amniotic cells at 14–17 weeks). If karyotype at late pregnancy became really necessary samples of fetal blood may be obtained by puncture of fetal umbilical cord (under guidance of ultrasound).
Practically, prenatal cytogenetic diagnosis is a very good method to reduce numerical abnormalities, mostly trisomies. Its role in detection of chromosomal disorders, caused by structural abnormalities is far less, because most women pregnant with fetuses having structural chromosomal defects are young and do not have biochemical indications for amniocentesis. The only (but very important) exceptions are families with structural chromosomal abnormalities in one of the parents. In these families prenatal diagnosis of the karyotype may be crucial for decision about fate of the pregnancy. Actually, the last group of families may benefit from preconceptional diagnosis. This method (or better these methods) may allow selection of normal egg–cells for further fertilization in vitro and implantation of the embryo with already known karyotype.