Introduction
Genetics is the branch of biology concerned with heredity and individual characteristics. Specific conditions and rare disorders may have a genetic basis. Where this is the case there will be a variety of causes. For example; the causes may include a single abnormal gene, a chromosomal abnormality or a genetic predisposition allied to other factors.
This section includes a glossary of genetic terms used throughout The Contact a Family Directory and it is written for the non-specialist. We shall concentrate mainly upon two forms of inheritance: the single abnormal gene and chromosomal abnormalities. Illustrations are used to explain certain patterns of inheritance.
The human body is made up of billions of cells. At the centre of each cell is a special compartment called the nucleus which stores threads of DNA (Deoxyribonucleic Acid) arranged in chromosomes. The chromosomes are in their turn composed of 50,000 to 100,000 genes which contain the genetic blue print determining each individual's characteristics.
The ovum and sperm each carry 23 chromosomes and on fertilisation the chromosomes combine to give a total of 23 pairs, 46 chromosomes in total. One pair of chromosomes determines the sex of the individual: males have an X and Y chromosome, while females have two X chromosomes.
Inheritance will depend upon the arrangement of the genes and the status mode of the gene: that is, autosomal dominant, autosomal recessive or X-linked recessive. (These terms are defined in the Genetics glossary).
1. Single abnormal gene
A mutant (abnormal) gene is one where a gene may be considered as a variant of a 'normal' gene. This change may occur spontaneously by chance and have no significance for the individual concerned. In other cases, the gene which mutates (changes its character) may give rise to specific inherited disorders where there is no previous family history. Such a gene, in specific circumstances determined by status, can cause a specific disorder. Inheritance may be autosomal dominant, autosomal recessive or X-linked recessive.
More research has shown that in many conditions there may be different spelling mistakes or mutations in the gene which can cause the disease. For example, in cystic fibrosis over 200 different mutations can occur in the gene, but they mostly produce the same disease pattern.
Autosomal dominant inheritance
Autosomal means that males or females are equally affected. In dominant inheritance the chance of passing on the disorder is 50% for each pregnancy. If the gene is inherited it will result in an affected individual. Examples of such conditions are Huntington's Chorea or Tuberous Sclerosis. In some cases penetrance may not be complete in some individuals, resulting in a mild form of the condition. Sometimes the condition with autosomal dominant inheritance may arise due to a mutation in egg or sperm, and in such cases there would be no preceding history.
Autosomal recessive inheritance
In this form of inheritance the affected gene is recessive: two of the same gene mutations are required for the child to be affected by the disorder. In such cases the parents are unwitting carriers of the gene. The risk of an affected child being born will be 25% for each pregnancy. Examples of such conditions are Friedreich's Ataxia, Cystic Fibrosis or Phenylketonuria.
Unless the parents are related, the chances of marrying a carrier of the same recessive gene is low, though the incidence of the existence of recessive genes in the population varies with condition. Genetic counselling can help to predict the occurrence for individual families.
X-linked recessive inheritance
This is a recessive form of inheritance where the mother carries the affected gene on the X chromosome. This means that girls are carriers and that usually only boys are affected by the disorder. Examples of such disorders are Duchenne Muscular Dystrophy, Haemophilia (Hemophilia - US) or Hunter disease (a mucopolysaccharide disease).
Affected men will not pass the condition on to their sons but all their daughters will be carriers. This is because a man passes his Y chromosome on to his sons and his X chromosome to his daughters.
In some rare situations, female carriers may show mild features of an X-linked disorder, for example in Fragile X syndrome.
X-lined dominant inheritance
There are few examples of this type of inheritance, one such is Coffin-Lowry syndrome. In this form males and females are both affected. An affected female will have a 50% chance of passing the disorder on to both her sons and her daughters. An affected male will pass the condition on to all his daughters, but not to his sons.
Mitochondrial inheritance
The genetic material (DNA) is largely located in the nucleus of the cell, but in the surrounding cytoplasm of the cell there are small bodies called mitochondria which are responsible for energy production and also carry their own genes and DNA. These genes can also be passed on during reproduction. However, the pattern of inheritance is not always predictable since there is a chance element in determining the amount of cytoplasm and hence the amount of mitochondrial DNA that is passed on. Mitochondrial DNA is passed on through the egg but not by the sperm as it is only the nucleus of the sperm that enters the egg during fertilisation. Hence the pattern we see with mitochondrial inheritance is transmission through an affected female to a variable number of male and female offspring, but no transmission from an affected male.
Imprinted genes
In most cases it will not matter whether the gene or chromosome defect is inherited from the mother or father - the effect on the child will be the same. However there are some genes and chromosome regions in which there will be a different effect depending on which parent the abnormality has come from. For example, a deletion of chromosome 15 from the father in the sperm will cause Prader-Willi syndrome whereas the same deletion of chromosome 15 from the mother in the egg will cause a different condition called Angelman syndrome . With these imprinted genes it is necessary to have both the maternal and paternal contribution in early embryonic development in the womb. It is likely that the need for a contribution from both parents has arisen in evolutionary terms with sexual reproduction and has been recognised as a barrier to certain forms of cloning.
2. Chromosomal abnormalities
A chromosome is a rod like structure present in the nucleus of all body cells, with the exception of the red blood cells, and which stores genetic information in the form of genes. The chromosome is like the wrapping round the genes. Normally human beings have 23 pairs of chromosomes, 46 in total. The ova and sperm carry one of each pair, 23 chromosomes each. On fertilisation the chromosomes combine to give a total of 46. One pair of chromosomes in each individual is designated XX or XY. Normally a female has an XX pair and a male an XY pair.
A chromosomal abnormality occurs when there is a defect in a chromosome or in the arrangement of the genetic material on the chromosome. Chromosomal abnormalities give rise to specific physical features, but it should be stressed that there may be wide variations in the severity of the symptoms in individuals with the same chromosome abnormality.
Additional material may be attached to a chromosome; absence of a whole or part of a chromosome may occur; and defective formation of the chromosome may also occur. Increases and decreases in chromosomal material interfere with normal body function and development. Chromosomal abnormalities give rise to specific physical features.
There are two main types of chromosomal abnormality which may occur during meiosis and fertilisation. These are known as numerical aberrations and structural aberrations.
Numerical aberrations
Where these occur there is a failure in chromosome division resulting in cells with an extra chromosome (24 chromosomes) or a deficiency (22 chromosomes). Such abnormal gametes can result in anomalies such as Down syndrome (47 chromosomes) or Turner syndrome (45 chromosomes). The following are examples of numerical aberrations; triploidy, trisomy, monosomy and mosaicism.
Karyotype 46,XX
Chromosome pattern in a female
Karyotype 46,XY,del(8)(p23)
A deletion of the short arm of chromosome 8 in a male
Karyotype 47,XX,+18
A Trisomy 18 in a female
Karyotype 46,X,r(X)
A ring formation of the X chromosome
Structural aberrations
Where these occur there is a rearrangement in the location of, or a loss of, genetic material. These include; deletions, duplications, inversions, ring formations and translocations (balanced, unbalanced and robertsonian).
When cultured under specific conditions fragile sites may be located on the X chromosome. This gives rise to Fragile X syndrome where boys are worse affected but one third of affected girls also have some degree of learning difficulty.
Descriptions of particular chromosomal formations are often written in a shortened form. This type of contraction indicates the total number of chromosomes, the sex of the individual and the abnormal chromosome number. For example a girl with Cri du Chat syndrome would be shortened to 46,XX,5p- that is, the affected child has 46 chromosomes, is a female (XX) and has a deletion of the short arm of chromosome 5. If this was in the form of a ring it would be 46,XX,r(5). A trisomy could be written as 47,XY, + 21, a male with Down syndrome .
Gene mapping is the area of genetic research that identifies at which chromosome site the gene is located. This is the first stage in trying to identify specific disease genes.
Gene markers are variations in the DNA or genetic material which lie close to the site of a disease gene and may be used for 'tracking' the disease through a family to provide prenatal or presymptomatic diagnosis.
Gene tracking is the process through which Gene Markers are followed through a family by genetic testing. When a specific marker is inherited with the disease in a significant number of individuals, then it may be used to assist in prenatal tests.
Fluorescent In Situ Hybridisation (FISH) is a new and promising technique for using fluorescent labelled gene markers in chromosome analysis. It allows the recognition of small deletions and rearrangement which would previously have been undetected. It may also provide a rapid method of detecting chromosome abnormalities.
3. Genetic pre-disposition allied to other factors
Such conditions combine a pre-disposition to develop a disease with other factors which may also contribute. There may be an undefined familial history of the condition. Where two affected children are born there may be an increased risk of recurrence. An example of a condition which falls into this category is Cleft Lip and Palate.
4. Genetic counselling
This is available at regional genetic centres throughout the country. Genetic counselling can quantify risks for particular parents in their individual circumstances. It can also provide support and advice for families who already have an affected child and wish to enlarge their family. Contact a Family also produces the guide 'A genetic condition in the family' which gives a brief introduction to genetics, explores what counselling involves and tries to address many of the worries and concerns that surround it.
Prenatal diagnosis
Pre-Natal Diagnostic Techniques
There are a number of techniques which are used to diagnose prenatal defects in fetuses whose mothers are at risk of having a baby with an abnormality. This may be a question of a family history of an anomaly, or that the parents have already had one child with, say, a heart defect. On the other hand prenatal testing may be performed on the grounds of the age of the mother. Common techniques are:
Amniocentesis
A sample of amniotic fluid (the 'waters') is taken through the abdominal wall. The sample of fluid is then analysed and certain biochemical, chromosomal or neural tube defects can be identified. Results may take three to four weeks. Amniocentesis can identify: metabolic diseases where the affected enzyme has been previously identified; chromosome defects; and neural tube defects (such as Spina Bifida).
Chorionic villus sampling
After fertilisation of the ovum by the sperm, the fertilised body forms a cell mass. The inner cells of this mass form the fetus, while the outer cells form the placenta. These outer cells become embedded in the wall of uterus (womb) forming placental material with same origin as the fetus. These chorion cells can be tested to indicate fetal abnormality.
A catheter is introduced through the vagina or abdominal wall and using ultrasound scanning is guided to the chorionic villi. This test can be performed at 10 to 12 weeks and chromosome results are available within two weeks. Hence results of abnormalities are obtained earlier than by amniocentesis.
The test can identify: metabolic defects where the affected enzyme has been isolated; chromosomal defects; and certain single gene defects where the specific gene has previously been identified. In these latter groups, results may be available in one or two days.
Fetoscopy
In this technique the mother and the fetus are both heavily sedated: and an endoscope is fed through the abdominal wall into the uterus. A needle is then inserted through the tube. This method allows samples of fetal blood, liver or skin to be taken.
The advantages of fetoscopy are that the fetus can be seen and tissue and blood sampled. Additionally therapy such as blood transfusion may be given. Fetoscopy has largely been superseded by early prenatal diagnosis and ultrasound. It is available only in a few specialist centres.
Ultrasound scanning
A widely used technique involving the use of ultrasonic waves (sound waves of a high frequency which cannot be heard by the human ear) to scan the fetus and measure it. The fetus can be seen on the screen enabling skeletal and other abnormalities to be identified. Fetal measurements taken at the scan can be compared with average 'normal' fetal age measurements to identify anomalies.
Scans are normally performed between 16 to 20 weeks. Conditions which may be identified include Spina Bifida, Hydrocephaly and Microcephaly. In some conditions like Tuberous Sclerosis, where heart tumours may contribute to the diagnosis, an additional scan may be performed at 20 to 22 weeks. The technique is widely used and has no specific risks for mother or fetus.
Medical text written 1991 by Professor Michael Patton. Last updated October 2004 by Professor Michael Patton. Last reviewed August 2005 by Professor Michael Patton, Professor of Medical Genetics, St George's Hospital Medical School, London, UK.
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