Genetics - Inheritance Patterns
How genetic disorders are inherited
Genetic disorders are usually caused by alterations to a chromosome (or part of a chromosome) or to a gene. A structural change to a chromosome will usually affect the function of a number of genes. At the time of cell division, sections of chromosomes can become detached. This detached part may be lost completely (deletions), it may re-attach the wrong way round (inversions) or it may become associated with material from another chromosome (various types of insertion and translocation). The Ectodermal Dysplasia (ED) syndromes are more often caused by alterations within a gene - spelling mistakes in the DNA code.
Alterations in the DNA sequence of the gene may be inherited from a parent or normal genes may become altered – they may mutate - at the time of egg or sperm formation or even afterwards, during the course of development. When a cell does not accurately copy its DNA, a mistake or variation in a single DNA letter (known as 'bases') may arise. The altered DNA sequence is likely to result in an altered protein being made and, if that protein is vital or crucial for the operations of the human body, abnormalities may occur.
It takes two to make a baby, so chromosomes and the genes they carry come in pairs; one set of 23 from the mother and one set of 23 from the father, making 46 in total. It is the chromosomes in the egg and sperm that carry the genetic information from one generation to the next. In the formation of sperm, one of each chromosome pair is placed into the developing sperm, and likewise for the egg, so each has a single set of 23 chromosomes.
When the egg and sperm come together at fertilisation, the proper number of 46 is restored, ready for the baby's development. Sometimes the process that leads to just one of the chromosome pair being placed in the egg or sperm goes wrong and the resulting child has 47 or 45 chromosomes. The most common chromosomal abnormality of this type is Down's syndrome, usually due to the egg having both copies of chromosome 21 so the affected child ends up with three. This overdose of gene action from chromosome 21 disturbs the genetic control of development.
Twenty-two of the chromosome pairs are the same in males and females, but the 23rd pair is different. The chromosome pairs that are the same in both sexes, numbered 1 to 22, are called autosomes to distinguish them from the sex chromosome pair, X and Y. Females have two X-chromosomes, whilst males have one X and one Y chromosome. This means that the sperm are of two types with respect to their chromosomes; half will have an X chromosome and half a Y chromosome. If an X-carrying sperm fertilises the egg, the baby will be a girl, whilst a Y-carrying sperm makes a boy. The father's contribution, the sperm, determines the sex of the baby.
Understanding how the chromosomes behave during egg and sperm formation has allowed us to explain the simplest patterns of inheritance of a character, or disease, as originally observed by Gregor Mendel in his study of peas over a century ago. There are three simple patterns of inheritance. The first two involve one of the pairs of genes on chromosomes 1 to 22 and are referred to as autosomal dominant and autosomal recessive inheritance. The third, sex-linked inheritance, involves one of the genes on the X-chromosome and for this reason is also called X-linked inheritance.
These three 'Mendelian' patterns of inheritance are illustrated here by way of simple chromosome diagrams depicting a single chromosome pair and just one gene upon it.
Autosomal dominant inheritance occurs when a single altered copy of the gene is enough to cause a problem in the person who carries it, despite that person having another, intact copy of the same gene. A person affected in this way will have a 50% (1 in 2) chance of passing the disorder onto each of their children regardless of the gender of the parent or the child.
Autosomal recessive inheritance occurs when the disease arises only when both copies of the relevant gene are altered. This almost always occurs when both parents are unaffected carriers of a gene alteration and both happen to pass on to the same child their altered copy of this gene. The child then does not have even a single unaltered copy of the gene – and so has a problem. Each parent will have a single copy of the abnormal gene and therefore the chance for them to have another affected child is 1 in 4.
This is because:
1 child in 4 gets a copy of the abnormal gene from each parent and is affected
2 children in 4 get a copy of the abnormal gene from one parent and a copy of a normal gene from the other parent, and therefore are carriers
1 child in 4 inherits a normal gene from each parent and is not affected
It is important to appreciate that chance has no memory; it is 50% (autosomal dominant) or 25% (autosomal recessive) with each and every pregnancy, regardless of what happened with earlier pregnancies.
X-Linked Recessive - Recognition that many genes, important for a variety of tissue functions, are carried on the X chromosome, whilst the Y chromosome only carries the gene for maleness but seems to do little else, has allowed us to explain X-linked inheritance, as depicted in this diagram. If a mutation in a gene on the X chromosome causes a problem, it will usually do so much more clearly in a male than a female. This is because a male has only one copy of any gene on the X chromosome, whereas a girl has two copies and therefore has a second X chromosome which carries a working copy of the gene that can compensate for the malfunction of the faulty gene.
Despite this, however, a mutation in a gene on the X chromosome can often show in a female because only one of the two genes will be active in any one cell in the body. In fact, a female has patches where she uses the genes on one X chromosome and other patches where she uses the genes on the other X chromosome. Just which X chromosome is active in any one area on the body is random – it is down to chance.
A New Mutation
Sometimes, a genetic disorder occurs spontaneously in an early embryo and there is no inheritance of the disorder from either parent. In this case the disorder is classed as a new mutation. When a child has an Ectodermal Dysplasia syndrome and the parents are confirmed by molecular diagnosis (through blood samples) not to be carriers of the syndrome, there is only a very small chance that the mutation will occur in another child of the same parents. The affected child however, will have a chance of passing the disorder onto their children.
A boy born to a carrier female has a 50% chance of being affected and a girl has a 50% chance of being a carrier, like her mother. All sons of an affected male will be unaffected (they get dad's Y chromosome), but all his daughters will be carriers (they get their dad's X-chromosome).
Statistical probabilities are all very well when being reassured by comfortingly low odds (often the case after genetic counselling), but it is not much help to those facing a high chance of an affected child. People often want to know whether they are a carrier or not; whether the developing baby is affected or not. All else is just agonising uncertainty. It has only been through the advances of molecular genetics that most carrier testing and early prenatal diagnosis have become possible.
Ectodermal Dysplasia syndromes can be passed down from generation to generation. However, the chances that a man and woman will have an affected child will depend on the inheritance pattern of the type of Ectodermal Dysplasia in that family.
The Ectodermal Dysplasia Society strongly advises individuals who have been diagnosed with an Ectodermal Dysplasia syndrome, as a carrier of an ED syndrome, and/or parents of children affected by an ED syndrome to seek genetic counselling. On this website we can provide a brief overview of the most common types of inheritance patterns but as each syndrome and inheritance pattern will be specific to each family, you are advised to speak with a Genetic Counsellor or Clinical Geneticist about the probability of passing Ectodermal Dysplasia onto future generations.
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