Consequences of Rare Chromosome Disorders

The effects of rare chromosome 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 chromosome 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 chromosome disorder is specified in as much detail as possible. The description of a person's chromosome make-up is called their GENOTYPE. Sometimes children with the same genotype will show similar problems. However, even children with the same genotype can differ in some or even nearly all of their problems. Why should this be? The genotype as seen under a light microscope is called a KARYOTYPE and only gives us the "big" picture. New technologies like array CGH analysis and next generation sequencing (NGS) allow us to look at chromosome and DNA changes at a much greater magnification and often show us that 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 genotype inherited as the result of a parent's chromosome rearrangement can still develop differently. There are many other factors besides a person's chromosome 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 chromosome 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 chromosome 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 chromosome 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 chromosome disorder in your baby or child. Nothing can be done about the actual chromosome defect because every single one of the billions of affected cells would have to have the missing chromosome material and all the genes involved added or extra chromosome material taken away and this is not possible yet with today’s technology. However, symptoms caused by the chromosome disorder can be treated as they arise and the best environment given in order for the child with the chromosome disorder to reach their full potential.

Cells, Chromosomes, DNA and Genes

When parents discover that their child has a rare chromosome 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 20,000 to 25,000 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 chromosome disorders, though, many 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.

Chromosomes & DNA Analysis

Specialist scientists called cytogeneticists examine a person's chromosomes or DNA for defects. Usually, they will analyse the chromosomes or DNA from the white cells (lymphocytes) in a person's blood. They can also analyse the chromosomes or DNA 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. For chromosome analysis down a microscope (karyotyping) 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. However, as the amount of material gained (duplicated) or lost (deleted) can often be extremely small and impossible to see on a routine chromosome test even by the most skilled of scientists, your child may have been told their chromosome analysis was normal. The clinician may have indicated that an underlying genetic basis was still likely. A newer test now available for looking at chromosomes is called a microarray-based comparative genomic hybridisation (also called an array CGH) test. Array CGH is an advance in technology that allows detection of chromosome imbalances that are smaller than can be detected through looking down the microscope. Karyotyping is only as good as the resolution of the microscope and is not able to detect subtle chromosome changes. These smaller alterations, often called submicroscopic alterations because they cannot be seen through the microscope, can still disrupt growth and development. These very small changes are often called microdeletions and microduplications. Array CGH is also sometimes called CGH array or simply a microarray. You can read more detail about Array CGH analysis in our information guide. Array CGH compares your child?s DNA with a control DNA sample and identifies differences between the two sets of DNA. In this way, deletions or duplications (imbalances) in your child?s DNA can be identified. From this, the gene content of any such imbalance can be established.

Karyotypes

As we have already mentioned, a person's chromosome 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 chromosome 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 2013 and it now includes nomenclature for molecular cytogenetic techniques such as FISH and microarrays. This means that anyone understanding the code will have a fairly precise description of a person’s chromosome disorder. In general, under the ISCN convention, karyotype codes are written so that the number of chromosomes in a person’s cells come first, followed by their sex chromosome make-up and then by a description of any chromosome disorder. Using this method, a normal male karyotype would be described as 46,XY and a normal female karyotypeas 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 is located. To help you understand this system more clearly, take a look at some examples of karyotype.

46,XX,del(8)(p23.1pter)

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.

47,XY,+9/46,XY

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 chromosome make-up. This is what we would call Trisomy 9 Mosaic.

46,XX,r(22)

This describes a female with 46 chromosomes, one copy of chromosome 22 being a ring chromosome. There is no indication given of the breakpoints.

46,XY,t(2;5)(p22;p15.1)

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 chromosome material has been lost or gained.

46,XY,der(5)t(2;5)(p22;p15.1) mat

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).

FISH & Microarray (array CGH) analysis

Instead of, or in addition, to a karyotype, you may be given the results of molecular analysis such as FISH or a microarray. Results of a FISH analysis might look something like this: 46,XY.ish del(9)(q34.3)(D9S2168-)dn This means:

46 The total number of chromosomes in your child’s cells
XY The two sex chromosomes, XY for males; XX for females
.ish The analysis was by FISH
del A deletion, or material is missing
(9) The deletion is from chromosome 9
(q34.3) The chromosome has broken at band 9q34.3, indicating a small deletion of the end of the chromosome just short of the 'telomere'
(D9S2168-) A marker or probe whose position on the human genome is known, in this case marker D9S2168, is missing
dn dn stands for de novo The parents’ chromosomes have been checked and no rearrangement found involving 9q34.3

With microarray analysis breakpoints at either end of a deletion or duplication are denoted either by the name of a DNA “clone” or by a base pair coordinate. A base pair is simply one of the “rungs” on the ladder of the double helix of DNA. The results are likely to read something like this: arr cgh 16p11.2(29581455->30106101)x1

This means:
arr cgh The analysis was by array-CGH
16p11.2 A change was found in band 16p11.2
(29581455->30106101)x1 This is a microdeletion with just one copy of this segment within band 16p11.2. The first base pair shown to be missing is number 29581455. The last base pair shown to be missing is 30106101. The microdeletion is 524,646 base pairs in size

You might already have been your child’s karyotype or the results of molecular analysis such as FISH or microarray and would like to work out exactly what the code means. If you do not know your child’s results, ask your doctor or geneticist for them, preferably with a copy of the original laboratory report(s), so that you have a correct description of your child’s chromosome disorder. Here is a list of the more common symbols used in karyotype descriptions and molecular analysis results.

Symbols used in Karyotypes

add Additional material of unknown origin
arr Microarray
arrow (->) From - to
Brackets, square [..] Surround number of cells
cen Centromere
cgh Comparative genomic hybridisation
single colon (:) Chromosome break
double colon (::) Chromosome break and reunion
comma (,) Separates chromosome numbers, sex chromosomes and chromosome abnormalities
decimal point (.) Denotes sub-bands
del Deletion
de novo Designates a chromosome abnormality which has not been inherited
der Derivative chromosome
dic Dicentric
dup Duplication
h Heterochromatin
i Isochromosome
idic Isodicentric chromosome
ins Insertion
inv Inversion
ish In situ hybridisation
mar Marker chromosome (extra chromosome of unknown origin)
mat Maternal origin
minus sign (-) Loss
MLPA Multiple ligation-dependent probe amplification
mos Mosaic
multiplication sign (x) Multiple copies of rearranged chromosomes or number of copies of a chromosome region
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
rea Rearrangement
rec Recombinant chromosome
rob Robertsonian translocation
s Satellite
semicolon (;) Separates altered chromosomes and breakpoints in structural rearrangements involving more than one chromosome
semicolon (;) Separates altered chromosomes and breakpoints in structural rearrangements involving more than one chromosome
slant line (/) Separates cell lines (used in mosaic karyotypes)
subtel Subtelomeric region
t Translocation
tel Telomere
ter Terminal (end of chromosome)
trp triplication
upd Uniparental disomy
var Variant or variable region
wcp Whole chromosome paint

Types of Rare Chromosome Disorders

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. Unique publishes information guides on many different individual chromosome disorders and these are freely available from our website or on request. For rarer chromosome disorders not covered by the guides, Unique might hold information in the offline database. Please contact us with your information requests.

NUMERICAL DISORDERS

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

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.

Translocations

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 chromosome 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

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

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 chromosome material but not both disorders.

Deletions and Microdeletions

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.

Rings

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 chromosome 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.

Duplications and Microduplications

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 chromosome segment, then this is known as a TRIPLICATION or a PARTIAL TETRASOMY. Some duplications are particularly small and are called MICRODUPLICATIONS.

Inversions

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 sSMCs

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 a small supernumerary marker chromosome (sSMC) 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.