Hemophilia is a bleeding disorder in which blood does not clot properly. Blood contains many proteins, called clotting factors, that can help to stop bleeding after injury or surgery. People with hemophilia have low amounts of either factor VIII (eight) or factor IX (nine), key factors responsible for normal blood clotting. Show
A person’s genes provide the instructions on how to make proteins, such as factor VIII and factor IX. In people with hemophilia, there is a mutation (difference from normal) in either the gene for the factor VIII protein or the gene for the factor IX protein. The mutation causes the body to produce too little factor VIII or IX. This change in a copy of the gene making factor VIII or factor IX is called a hemophilia allele. Most people who have hemophilia are born with it. It almost always is inherited (passed down) from a parent to a child. Both hemophilia A and B are inherited in the same way, because both the genes for factor VIII and factor IX are located on the X chromosome (chromosomes are structures within the body’s cells that contain the genes). The X and Y chromosomes determine whether a person’s sex is male or female; females have two X chromosomes (XX) and males have one X chromosome and one Y chromosome (XY). There are no genes for clotting factors on the Y chromosome. This means that males only have one allele for factor VIII and one allele for factor IX. Thus, if a male has a hemophilia allele on his only X chromosome, he will have the disorder. A female inherits two copies of the factor VIII or factor IX gene, one from her mother and one from her father. A female with a hemophilia allele on one X chromosome usually has a normal allele on her other X chromosome that can produce normal clotting factor, so she has some protection against having hemophilia. A female with one hemophilia allele and one normal allele is called heterozygous or a carrier. Some girls and women who are heterozygous have bleeding symptoms, but usually they are milder than those of boys and men with hemophilia. In rare cases, a female who is heterozygous can have bleeding symptoms that are just as serious as those of a male with hemophilia. A female can also have hemophilia if she inherits hemophilia alleles from both of her parents or if she inherits one hemophilia allele and her other X chromosomes is missing or does not work properly. Hemophilia may be hidden in a family for many generations if it passes only through females who do not have bleeding symptoms. If a mother is heterozygous (a carrier) for hemophilia and the father does not have hemophilia, each son has a 1 in 2 (50%) chance of getting his mother’s hemophilia allele and having hemophilia. Each daughter has a 1 in 2 (50%) chance of getting her mother’s hemophilia allele and being heterozygous. Overall, there is a 1 in 4 (25%) chance for each pregnancy that the baby will be a son with hemophilia and a 1 in 4 (25%) chance that the baby will be a heterozygous daughter. There is a 1 in 2 (50%) chance that the baby (either a son or a daughter) will not get the hemophilia allele at all and, therefore, can’t pass it down to his or her children.  A father who has hemophilia passes his only X chromosome down to all of his daughters, so they will always get his hemophilia allele and be heterozygous (carriers). A father passes down his Y chromosome to his sons; thus, he cannot pass down a hemophilia allele to them. Without the hemophilia allele, the sons will not have hemophilia and can’t pass it down to their children. Overall, there is a 1 in 2 (50%) chance that the child will be a son who does not have hemophilia and a 1 in 2 (50%) chance that the child will be a daughter who is heterozygous (a carrier). This is true if the mother does not have a hemophilia allele herself. That would be very rare, unless the parents are related.
A carrier, as related to genetics, is an individual who “carries” and can pass on to its offspring a genomic variant (allele) associated with a disease (or trait) that is inherited in an autosomal recessive or sex-linked manner, and who does not show symptoms of that disease (or features of that trait). The carrier has inherited the variant allele from one parent and a normal allele from the other parent. Any offspring of carriers is at risk of inheriting a variant allele from their parents, which would result in that child having the disease (or trait).
Carrier. The key to understanding carrier in the genetic sense is that, even though we all have two copies of each gene, for some genes you can have only one working copy and essentially have no major medical issues. The challenge arises when you have a child with another person who is also a carrier for the same autosomal recessive disorder, and the child inherits both nonworking copies from each parent. There's a 25% chance of this happening with every pregnancy. Most often, people don't know that they are carriers. As a result, it's now possible to genetically screen prospective parents to determine whether they are carriers for any of the more commonly seen autosomal recessive disorders.
How are hemophilia A and B inherited (passed)?The gene with the instructions for making factor is found only on the sex chromosome labeled X. If the gene is faulty, the result is hemophilia unless there is a dominant, normal gene on a matching X chromosome. Hemophilia is a sex-linked recessive disorder. These kinds of defects occur more often in men than in women. This section will explain all of this in more detail. What is a hemophilia carrier?A daughter gets an X chromosome from her mother and an X chromosome from her father. Suppose the X chromosome from her mother has the gene for normal blood clotting. Suppose the X chromosome from her father has the gene for hemophilia. The daughter will not have hemophilia since the normal blood clotting gene from her mother is dominant. It won't allow the instructions from the hemophilia gene to be sent. The daughter is called a carrier for hemophilia. She has the gene on one of her X chromosomes and could pass it on to her children. Does this mean that the mother alone is the one responsible for having a child with hemophilia? Not really. The mother is the one who passes the hemophilia gene. However, it is the father's sperm that determines if the child will be a boy or a girl. It is not the "fault" of one parent since both parents contribute to the outcome.All of us have dozens of abnormal genes. We are unaware of most of them. It is purely by chance that a hemophilia gene is passed on to produce a child with hemophilia. What are the chances of having a child with hemophilia?
These four points are explained below. The percentage (%) or "risks" are based on large numbers of births. In other words, if 500 carriers each had two sons (1,000 total), we would expect there to be about 500 boys with hemophilia. But in that group there would be women who had two sons with hemophilia, women who had one with and one without, and women with no sons with hemophilia. The gene a child will inherit is based purely on chance and can never be truly predicted. A child's chances of getting a hemophilia gene do not have anything to do with whether or not brothers or sisters have the gene. Each time a woman is pregnant, her chances of having a child with the hemophilia gene are the same (Figure 2-3). It is like rolling dice. The results of one roll do not affect the next roll. A family may have children with the hemophilia gene and children without it. It is also possible for all the children in the family to inherit the normal gene or all to inherit the hemophilia gene. Figure 2-3. For a mother who carries the hemophilia gene, the chances of giving birth to a child with hemophilia are the same for each pregnancy. Even though she already has a child with hemophilia, she can still give birth to another. What are the chances of having a baby with hemophilia or who is a carrier if:
The father's sex chromosomes are labeled XY, with the X chromosome carrying the hemophilia gene. [In our drawings, we have shown this by putting an H for hemophilia over the X.] The father only passes half of his sex chromosomes to the baby, either the X or the Y. If the baby gets the Y chromosome from the father it will be a boy. Since the Y chromosome does not carry the hemophilia gene, a son born to a man with hemophilia and a woman who is not a carrier will not have hemophilia. If the baby gets the X chromosome from the father it will be a girl. The X chromosome from the father with hemophilia will have the hemophilia gene. But the girl also gets an X chromosome from her mother. The normal blood clotting gene on the X chromosome from the mother is dominant, so the baby girl will not have hemophilia. She will, however, be a hemophilia carrier since she has the hemophilia gene on one of her X chromosomes. So in this case, all sons born to the couple will be normal and all daughters will be hemophilia carriers (Figure 2-4). Figure 2-4. Father with hemophilia; mother with normal blood clotting gene. Follow the arrows to see the possible gene combinations. What are the chances of having a baby with hemophilia or who is a carrier if:
The father's sex chromosomes are labeled XY. The father only passes half of his sex chromosomes to the baby, either the X or the Y. If the baby gets the Y chromosome from the father it will be a boy. The son can get from the mother either her X chromosome with the hemophilia gene or her X chromosome with the normal blood clotting gene. If the son gets his mother's X chromosome with the hemophilia gene he will have hemophilia. If he inherits his mother's other X chromosome, he will have normal blood clotting. So a carrier's son has a 50% chance of having hemophilia. A baby girl will inherit an X chromosome with a dominant gene for normal blood clotting from her father. So the daughter will not have hemophilia. A daughter will get either her mother's X chromosome with the hemophilia gene or her mother's X chromosome with the normal gene for clotting. If she gets the X chromosome with the hemophilia gene she will be a carrier. So a carrier's daughter has a 50% chance of being a carrier. A woman who is a carrier has:
Figure 2-5. Father with normal gene; mother a carrier. Follow the arrows to see the possible gene combinations. What are the chances of having a baby with hemophilia or who is a carrier if:
The father's sex chromosomes are labeled XY, with the X chromosome carrying the hemophilia gene. The father only passes half of his sex chromosomes to the baby, either the X or the Y. If the baby gets the Y chromosome from the father it will be a boy. If the boy gets his mother's X chromosome with the hemophilia gene he will have hemophilia. If he inherits his mother's other X chromosome, he will have normal blood clotting. If the baby gets the X chromosome from the father it will be a girl. The X chromosome from the father with hemophilia will have the hemophilia gene. The girl also gets an X chromosome from her mother. If she gets the normal X chromosome, the girl will be a carrier. If she gets the X chromosome with the hemophilia gene, she will have hemophilia. A man who has hemophilia and a woman who is a carrier have:
This is shown in Figure 2-6. It is very rare for a man with hemophilia and a woman who is a carrier to get together. That is why there have been only a few girls born with hemophilia. Figure 2-6. Father with hemophilia; mother a carrier. Follow the arrows to see the possible gene combinations. How could hemophilia appear in a family that has no history of the disorder?In some families, there is no known family history of hemophilia. The hemophilia gene seems to appear from nowhere and the family is shocked and confused. There are several reasons this could happen. First, the family may not know about or may have forgotten ancestors with hemophilia. Second, the gene for hemophilia may have been passed down by carrier females without anyone knowing. For several generations, the women may have had no boy children or by chance had only normal boys. No one would have known about the hemophilia gene. Third, hemophilia may appear in families with no history of it if the normal blood clotting gene suddenly becomes messed up (a spontaneous genetic mutation). What is a gene mutation?Normally, genes are exactly copied generation after generation. Sometimes, though, a gene may become faulty. It may give different or wrong directions to the body. This change in the gene is called a mutation. The change is permanent - the gene won’t be able to turn back to normal. The effects of the faulty gene may be noticed right away. Or they might not be seen until the gene is passed on to a baby. So the change in the gene may have happened in the parent or in the baby. The change in the gene can be caused by something in the environment. It also seems to happen without any clear cause. Since they are nature's way of bringing about change, not all gene mutations are harmful. The hemophilia gene can occur in a man or woman this way. The blood clotting gene suddenly becomes faulty. The gene may be passed by female carriers for several generations before hemophilia appears in a boy baby. If men with hemophilia and women who are carriers stopped having children, would hemophilia disappear forever?Probably not. Mutations in blood clotting genes would still happen, making new carriers and new people with hemophilia. It is believed that as many as one-third of the babies born with hemophilia are caused by new gene mutations. Once hemophilia is in a family, will it always be there?Once the hemophilia gene is present, the chance of passing it on exists. It is possible, however, for hemophilia to disappear from the family tree. This can happen if all family members who have hemophilia or who carry the hemophilia gene give birth to children who by chance do not get the gene. Can people with hemophilia in a family have different clotting factor levels (mild, moderate, or severe)?The clotting factor level will be about the same from one generation to the next. So the daughters of a man with severe hemophilia will all carry the gene for severe. It won’t change to mild or moderate. The same goes for men with mild and moderate hemophilia. Their children will all carry the same level. Even though the level stays the same, hemophilia can have very different effects on the lives of people in the family. This is due to different lifestyles and treatments for hemophilia. For instance, a grandfather with hemophilia may have very bad joints and walk with a limp because he could not get treatment when he was young. His grandson may be running track on his high school team because early treatment with factor has kept his joints healthy. |
What is the probability (%) of having a child that is affected by an autosomal recessive disorder if both parents are not carriers?
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