Chromosomes and Rare Chromosome Disorders in General
Author Beverly Searle BSc(Hons) PhD CBiol MSB
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Rare chromosome disorders include extra, missing or re-arranged chromosome material but do not include the more common chromosome conditions such as Down's Syndrome. Using the latest technology, it is now possible for smaller and more complex chromosome defects to be identified. The amount of chromosome material duplicated, missing or re-arranged can vary a great deal. This means that it may be difficult to identify two people who have exactly the same chromosomal disorder. The clinical problems of those affected can also vary enormously even when the chromosome diagnoses are similar.
Individually rare chromosome disorders are indeed very rare but collectively they are common. In fact one in every 200 babies is born with a rare chromosome disorder, one in every 1,000 babies having symptoms from birth or early childhood, the rest being affected when they grow up and try to have babies of their own. They may have multiple miscarriages, fertility problems, stillbirths or the birth of a disabled child. Some of these chromosome disorders are so rare that they are actually unique. It is usually immediately following diagnosis that affected families and individuals have the greatest need for emotional and practical support and above all, for information. But even among the more common "rare" disorders, it is likely that the professionals in the local community - the GP, Social Worker or even hospital specialists - will have never before come across anyone with the same disorders. The usual sources of support are not available to affected families, yet the effects of the disorders can be devastating. The vast majority of families have a desperate feeling of isolation. Under the umbrella of Unique membership, families can benefit from mutual support and linking even though the chromosome disorders may be quite different.
General information on chromosomes and rare chromosome disorders can be found below or in our Little Yellow Book.
The effects of rare chromosomal disorders can be very varied. The vast majority of carriers of balanced rearrangements will have no symptoms but might have problems in reproduction. Where there has been a loss or gain of chromosomal material, the symptoms arising might include a combination of physical problems, health problems, learning difficulties and/or challenging behaviour. The combination and severity of effects occurring very much depend upon which parts of which chromosomes are involved. The outcome for the affected children can be quite different. In general,
loss of a segment of a chromosome is more serious than the presence of an extra copy of the same segment. Defects of chromosomes 1 to 22 are usually far more serious than those of the sex chromosomes X and Y. It is very important that a child's chromosomal disorder is specified in as much detail as possible. The description of a person's chromosomal make-up is called their KARYOTYPE. Sometimes children with the same karyotype will show similar problems. However, even children with the same karyotype can differ in some or even nearly all of their problems. Why should this be? The karyotype only gives us the "big" picture as seen under a light microscope. If you were able to look at a much greater magnification, the actual breakpoints in the chromosome might be many genes apart. But even that does not explain all the differences. Even brothers and sisters with the same karyotype inherited as the result of a parent's chromosomal rearrangement can still develop differently. There are many other factors besides a person's chromosomal disorder that affect how they develop, for example, the unique mixture of genes on their other normal chromosomes, the environment in which they are raised and so forth. Sometimes a particular chromosome disorder will give a similar pattern of problems. If enough children are born with this similar pattern, then this can be called a SYNDROME. There are also some general characteristics of rare chromosomal disorders that occur in the majority of affected people to varying degrees. For instance, most people with any loss or gain of material from chromosomes 1 to 22 will have some degree of learning disability and developmental delay. This is because there are many genes located across all these chromosomes that code for normal development of the brain. Defects in any one of them could have a harmful effect on normal development. You might have been dismayed if the doctors and geneticists that you have consulted about your child's chromosomal disorder are not able to give
you a definite idea of how your child will be affected in the long term, especially if the disorder is particularly rare. You might think that the doctors simply do not want to help or can't be bothered to find out. Nothing could be further from the truth. The point is that, like any other child, your child is UNIQUE and while there might have been other similar chromosomal disorders reported in the medical literature, it does not mean to say that your child will develop in the same way. Like any of us, doctors do not have a crystal ball to look into the future. They might only be able to give you an idea of the possible problems that might arise. You, or your family and friends, might have asked what can be done to "cure" a chromosomal disorder in your baby or child. Nothing can be done about the actual chromosomal defect because every single one of the billions of affected cells would have to have missing chromosomal material added or extra material taken away and this is just not possible. However, symptoms caused by the chromosomal disorder can be treated as they arise and the best environment given in order for the child with the chromosomal disorder to reach their full potential.
When parents discover that their child has a rare chromosomal disorder, they often find themselves confronted with a very steep learning curve. Any information learnt about genetics in biology classes at school may be a distant memory. Here we will try to provide you with the basic facts about chromosomes and the different types of rare chromosome disorders. If you find the information a bit complicated, please don't be put off but do ask if you aren't sure what anything means.
The human body is made up of billions of individual CELLS. With the exception of the red blood cells, each of these cells contains a structure called the NUCLEUS, which is held within a thick fluid called the CYTOPLASM. Inside the nucleus are found the CHROMOSOMES, which contain the GENES. Genes are "strung" along the chromosomes, a bit like beads along a necklace. Genes are the instructions that tell
the body how to develop and work properly. Apart from the mother's EGG cells or the father's SPERM cells, every cell in the human body normally contains 23 PAIRS of chromosomes, making 46 chromosomes in total in each cell. This number of chromosomes is known as the DIPLOID number. The Human Genome Project has shown there to be about 30,000 genes in every cell. These genes are spread unevenly across the chromosomes, some chromosomes having many more genes than other chromosomes and some parts of each chromosome holding more genes than other parts. Of the 23 pairs
of chromosomes in each of these cells, one member of each pair is normally inherited from the father and the other member is normally inherited from the mother. Members of each pair of chromosomes are called HOMOLOGOUS chromosomes. The first 22 pairs of chromosomes are called the AUTOSOMES and are numbered from 1 to 22 according to their length, starting with number 1 as the longest. The chromosomes in the 23rd pair are called the SEX CHROMOSOMES. Sex chromosomes are labelled X or Y. Males normally have one copy of the X chromosome and one copy of the Y chromosome in
each cell; it is the Y chromosome that determines "maleness". Females, on the other hand, normally have two copies of the X chromosome but no Y chromosome. The number of chromosomes in the egg or sperm is different from that in other body cells. The mother's eggs each contain only 23 chromosomes (the HAPLOID number), made up of one copy of each autosomal chromosome (1 to 22) along with one copy of the X chromosome. The sperm from the father also contain 23 chromosomes, again made up
of one copy of each autosomal chromosome but also either one copy of the X chromosome or one copy of the Y chromosome. So it is the father's sperm that determines whether a child will be a boy (XY) or a girl (XX).Under the microscope, chromosomes look like long, thread-like bodies. They have a SHORT ARM
(labelled "p", which stands for petit, the French word for small) and a LONG ARM (labelled "q"). Linking the two arms is a narrower region called the CENTROMERE. The ends of the chromosomes are called the TELOMERES. The telomeres stop the chromosome from unravelling, a bit like the plastic tips of a shoe-lace. Chromosomes are so named because they are able to take up certain dyes or stains. "Chromos" is the Greek word for coloured and "soma" is the Greek word for "body". Different stains give each chromosome a particular pattern of light and dark bands. It is the location of the centromere and the specific banding pattern of a chromosome that allows it to be identified. Chromosomes are built up of a chemical called DNA (DeoxyriboNucleic Acid) and some proteins. Genes are composed of small stretches of some of the DNA in chromosomes. The DNA is held in a twisted shape called a DOUBLE HELIX. This double helix is tightly coiled but these coils are then coiled again and then yet again, a bit like if you twist a shoe-lace until it is coiled tightly into a ball. If you uncoiled all the DNA in just one diploid cell until it was pulled out to its fullest extent, it would measure around two metres! If all the DNA from the billions of cells in a mature adult human were stretched out end to end, it could be wrapped around the Equator up to 5 million times! DNA has two very important jobs. It works very much like an assembly line in a factory. It acts as the TEMPLATE or blueprint for assembly of all the proteins in our bodies. When most people think of protein, they tend to think of it as an important part of the food they eat or as a major component of the structure of their muscles. While some proteins are indeed very important as part of the structure of our bodies, others have essential parts to play in controlling how our bodies work properly. Some proteins act as enzymes, which make the chemical reactions in our bodies happen more easily and quickly, while others act as hormones, which help control our body's proper functioning and development. Some proteins even help control the production of other proteins by different genes. The process of protein production is a very complex one and yet, most of the time, the correct proteins are made to keep our bodies working properly and healthily. With rare chromosomal disorders, though, many thousands of genes might be missing or extra and so essential proteins are either not made at all or are made in too many copies or are made incorrectly or at the wrong time. The second important function of DNA is to pass on the genetic blueprint from old cells to new cells and from parent to child. An accurate copy of the DNA in each chromosome has to be made every time a new cell is formed.
Specialist scientists called cytogeneticists examine a person's chromosomes for defects. Usually, they will analyse the chromosomes in the white cells (lymphocytes) in a person's blood. They can also analyse the chromosomes found in the cells of other body tissues like bone marrow or skin or they might analyse the cells from chorionic villus or amniotic fluid samples to see if a fetus is carrying an abnormality. The cell samples have first to be grown up under special laboratory conditions and this can be very time-consuming, especially if amniocentesis samples are to be analysed. This is one reason why it can take several weeks for the results of a chromosome analysis to be reported. Cytogeneticists will use special chemicals to stop the cells they are examining at an appropriate stage when the chromosomes are at their most compact. At this stage, called METAPHASE, the chromosomes can be stained with different dyes. The stain used most often is called GIEMSA in a technique producing G-BANDED chromosomes. Different stains give the chromosomes a characteristic pattern of light and dark bands which helps with their identification. Sometimes the chromosomes are analysed when they are a little less compact so that more bands can be seen and smaller extra or missing pieces of DNA can be identified. This is called High Resolution Analysis. Diagrams of chromosomes showing these banding patterns are called IDEOGRAMS. Other newer analytical techniques have been developed which are used in addition to these staining methods. These newer techniques include, for example, Fluorescent In-Situ Hybridisation (FISH) and microarray-CGH. Take a look at our Conference Report 2005 for more information about chromosome analysis.
As we have already mentioned, a person's chromosomal make-up is called their KARYOTYPE. Obviously, it would be impractical always to have to show a photograph of someone's chromosomes in order to describe precisely any chromosomal disorder they might have. As a consequence, cytogeneticists have devised a standardised code to describe a person's karyotype. This system is called the International System for Human Cytogenetic Nomenclature (ISCN). The most recent version was published in 2005. This means that anyone understanding the code will have a precise description of a person's chromosomal disorder. In general, the ISCN code is written so that the number of chromosomes in a person's cells comes first, followed by their sex chromosome make-up and then by a description of any chromosomal disorder. Using this method, a normal male karyotype would be described as 46,XY and a normal female karyotype as 46,XX. Any breakpoints in chromosomes are described by a standardised numbering system based on the banding patterns produced in G-banded chromosomes. The bands allow the chromosomes to be mapped into REGIONS, which in turn are divided into BANDS and then into SUB-BANDS. This is a bit like being able to identify a house along a road if you know the house number. With the ISCN numbering system, the higher the number of the breakpoint, the further away from the centromere it can be found. To help you understand this system more clearly, take a look at some examples of karyotype descriptions.
This karyotype tells us that this person has 46 chromosomes in each of their cells. The person has two X chromosomes and so is a female. The "del" stands for deletion and so the female has a deletion of part of chromosome 8. The chromosome has broken in the short arm ("p") at region 2, band 3, sub-band 1 and the rest of the short arm up to the terminus or end (pter) is missing. So band 8p23.1 is the BREAKPOINT in this deletion.
This describes a male (X and Y chromosomes present) with 47 chromosomes in one cell line, the extra chromosome being a complete copy of chromosome 9, with a second cell line with a normal chromosomal make-up. This is what we would call Trisomy 9 Mosaic.
This describes a female with 46 chromosomes, one copy of chromosome 22 being a ring chromosome. There is no indication given of the breakpoints.
This describes a male with 46 chromosomes and a balanced reciprocal translocation between chromosomes 2 and 5 with breakpoints at bands 2p22 and 5p15.1. The segments 2p22 to 2pter and 5p15.1 to 5pter have swapped places with each other but no chromosomal material has been lost or gained.
This describes a male with 46 chromosomes and an unbalanced translocation involving chromosomes 2 and 5. One chromosome 5 is a derivative (der) chromosome with loss of part of the short arm from band 5p15.1 to 5pter. An extra piece of chromosome 2 from 2p22 to 2pter has been attached to the derivative chromosome at 5p15.1. This means that the person with this unbalanced translocation has a deletion of part of chromosome 5 combined with a duplication of part of chromosome 2. The translocation has arisen as
a result of a balanced translocation in the mother (mat). You might already have been given your own child's karyotype and would like to work out exactly what the code means. If you do not know your child's karyotype, ask your doctor or geneticist so that you too have a proper description of your child's chromosomal disorder. Here is a list (Table 1) of the more common symbols used in karyotype descriptions.
- add Additional material of unknown origin
- arrow (->) From - to
- cen Centromere
- single colon (:) Chromosomal break
- double colon (::) Chromosomal break and reunion
- comma (,) Separates chromosome numbers, sex chromosomes and chromosome abnormalities
- decimal point (.) Denotes sub-bands
- del Deletion
- de novo Designates a chromosomal abnormality which has not been inherited
- der Derivative chromosome
- dic Dicentric
- dup Duplication
- i Isochromosome
- idic Isodicentric chromosome
- ins Insertion
- inv Inversion
- mar Marker chromosome (extra chromosome of unknown origin)
- mat Maternal origin
- minus sign (-) Loss
- mos Mosaic
- p Short arm of chromosome
- parentheses ( () ) Surround structurally altered chromosomes and breakpoints
- pat Paternal origin
- plus sign (+) Gain
- psu Pseudo
- q Long arm of chromosome
- question mark (?) Questionable identification of a chromosome or chromosome structure
- r Ring chromosome
- rcp Reciprocal
- rec Recombinant chromosome
- rob Robertsonian translocation
- semicolon (;) Separates altered chromosomes and breakpoints in structural rearrangements involving more than one chromosome
- slant line (/) Separates cell lines (used in mosaic karyotypes)
- t Translocation
- tel Telomere
- ter Terminal (end of chromosome)
- trp triplication
Some changes or mutations in chromosomes are so small they only affect a single gene and these are known as single gene disorders. However, when changes in chromosomes are large enough to be seen using a light microscope, they are called chromosome aberrations or disorders. Visible disorders usually involve many genes and can be classified into two main types, NUMERICAL DISORDERS and STRUCTURAL DISORDERS. If these disorders arise during the formation of the egg or the sperm cells, then the disorder would be passed on to every cell in the body of a child produced. If the disorder arises in one of the new cells produced soon after the egg has been fertilised by the sperm, then only a proportion of the child's cells will be affected and this is called MOSAICISM.
If cells carry complete extra sets of chromosomes, this is known as POLYPLOIDY. When there is one extra set, to give 69 chromosomes in total, this is called TRIPLOIDY. If only some of the body's cells carry the extra set of chromosomes, then this is known as Triploid Mosaicism, or Diploid Triploid Mosaicism or even Mixoploidy. When individual whole chromosomes are missing or extra, this is called ANEUPLOIDY. This can happen with any of the autosomal chromosomes (1 to 22) or the sex chromosomes (X and Y). If one extra complete chromosome is present, this is known as TRISOMY and the number of chromosomes in each affected cell would be 47. Probably the most well-known example of Trisomy is Down Syndrome (Trisomy 21). Two extra complete chromosomes would be called TETRASOMY and the number of chromosomes would be 48. If a complete chromosome is missing, this is known as MONOSOMY and the number of chromosomes in each cell would be 45.
Structural disorders occur because of breakages in a chromosome. They can occur spontaneously (this is called DE NOVO) or they can be inherited from a parent. Structural disorders include various types of translocation, deletions, ring chromosomes, duplications, inversions and isochromosomes.
A translocation happens when DNA is transferred from one non-homologous chromosome to another. They include reciprocal translocations, Robertsonian translocations and insertional translocations. Translocations can be balanced or unbalanced.
Balanced Reciprocal Translocations and Unbalanced Translocations
Balanced reciprocal translocations as a whole are thought to occur at a rate of about 1 in 500 in the general population. Balanced reciprocal translocations happen when breaks occur in two or more different chromosomes and the resulting fragments of DNA swap places. No chromosomal material has been lost or gained and so the vast majority of carriers of a balanced reciprocal translocation do not have any symptoms. There can be rare exceptions to this. Symptoms can occur occasionally when children are born with de novo balanced reciprocal translocations, especially when more than two different chromosomes are involved. This is thought to be due, at least in part, to disruption of important genes at the chromosome breakpoints. However, if the child carries the same
balanced reciprocal translocation as their symptomless parent, then they should also not experience symptoms caused by the translocation. The problems with balanced reciprocal translocations arise because carriers are at risk of producing offspring with part of one chromosome missing and part of another extra. Such translocations are unbalanced and may lead to miscarriage or the birth of children with symptoms including learning difficulties and physical disabilities. Balanced reciprocal translocations tend to be unique to individual families and so it is very important that families consult a genetic counsellor
so that the specific risks of miscarriage and bearing children with disabilities can be discussed.
Robertsonian translocations occur when the short arm of certain chromosomes (chromosomes 13, 14, 15, 21 or 22) are lost and the remaining long arms fuse together. Loss of the short arms of these chromosomes should not cause any symptoms. A person with a Robertsonian translocation has a total chromosome number of 45. Robertsonian translocations are relatively common in the general population (about 1 in 1000), the most frequent being fusion of the long arms of chromosomes 13 and 14. The significance of a Robertsonian Translocation is the risk of miscarriage or of producing children with an unbalanced chromosome make-up.
Insertions occur when a segment of one chromosome is inserted into a gap in another chromosome. If someone carries a balanced insertional rearrangement, they should not have any symptoms (unless a critical gene is disrupted at the breakpoints) but they are at risk of producing a child with either a deletion or a duplication of chromosomal material but not both disorders.
A DELETION involves loss of a part (a segment) of a chromosome and is sometimes known as a PARTIAL MONOSOMY. Deletions can occur in any part of any chromosome. If the segment is lost from near to the centromere, this is called a PROXIMAL DELETION. If the segment is lost from nearer to the end of the chromosome (the telomere), then the deletion is called a DISTAL DELETION. If there is just one break in the chromosome, then the deletion is called a TERMINAL DELETION. (Terminal just refers to the end of the chromosome and does not infer that the deletion will be lethal to the child.) If there are two breaks in the arm of the chromosome with the intervening segment being lost and the remaining parts of the chromosome joining up, then this is called an INTERSTITIAL DELETION. Some deletions are particularly small and are called MICRODELETIONS.
A RING chromosome usually forms when the ends of both arms of the same chromosome are deleted. The remaining broken ends of the chromosome are "sticky" and join together to make a ring shape. Usually it is the missing DNA that is significant. In effect, the person with a ring chromosome has a terminal deletion of both the short and the long arms of the chromosome. However, if the ring chromosome is present as an extra (or SUPERNUMERARY) chromosome, then it is the chromosomal material that has NOT been deleted that is significant. The material in the extra ring chromosome has effectively been duplicated. Some geneticists believe that there can also be a general effect caused by any ring chromosome, poor growth and developmental delay being the outcome.
A DUPLICATION occurs when an extra copy of a segment of a chromosome is present. A duplication is sometimes known as a PARTIAL TRISOMY. If a person has two extra copies of a chromosomal segment, then this is known as a TRIPLICATION or a PARTIAL TETRASOMY.
Inversions occur when there are two breaks in a single chromosome. The segment between the breakpoints turns through 180 degrees and reinserts itself into the "gap" left in the chromosome. If both breaks occur in the same arm of the chromosome, this is called a PARACENTRIC INVERSION. If one break occurs in the short arm and the other in the long arm of the chromosome, then this is called a PERICENTRIC INVERSION. Usually, inversions do not cause problems in the carrier (unless important
genes are disrupted) but there is a risk of producing sperm or eggs with unbalanced chromosomes. Carriers of paracentric inversions very rarely give birth to children with abnormalities. On the other hand, carriers of pericentric inversions more frequently give birth to children with abnormalities. These children will have a partial duplication of one arm of the affected chromosome along with a partial deletion of the end of the other arm of that chromosome or vice versa. The closer the breakpoints are to the ends (telomeres) of the chromosomes, the greater the chance of the child surviving to birth. This is because the chromosome segments deleted and duplicated will be smaller.
Isochromosomes and ESACs
Sometimes people carry an extra or supernumerary chromosome made up of parts of one or more chromosomes. They will effectively carry a duplication or triplication of the material forming this extra chromosome. If the origin of the extra chromosome is unknown, it is sometimes referred to as an extra structurally abnormal chromosome (ESAC) or a marker chromosome. If the extra chromosome is made up of two copies of the same segment of a chromosome, this is called an isochromosome. When these extra chromosomes carry two copies of the same centromere, they are called isodicentric chromosomes.