Hemophilia is a genetic disorder that prevents blood from clotting properly, which can lead to prolonged or spontaneous bleeding episodes. This condition arises from a problem with the production of specific proteins in the blood known as clotting factors. The genes that contain the instructions for making these factors have a variation, or mutation, that impairs their function. Understanding how this mutation is passed down through generations is crucial for families affected by the disorder.
X-Linked Recessive: The Inheritance Type for Hemophilia
Hemophilia A and Hemophilia B, the two most common forms of the disorder, share the same pattern of inheritance: X-linked recessive. “X-linked” means the gene mutation responsible for the condition is physically located on the X chromosome, one of the two sex chromosomes. The term “recessive” describes how the gene mutation must be present to cause the disorder in an individual. For females, who possess two X chromosomes, the condition is typically masked by a healthy gene on the second X chromosome. For males, who only have one X chromosome, inheriting a single copy of the mutated gene is enough to express the condition.
How X-Linked Inheritance Works
The mechanism of X-linked inheritance is directly tied to the biological difference between male (XY) and female (XX) sex chromosomes. Males are more frequently affected by hemophilia because they only inherit one X chromosome, which comes from their mother, and one Y chromosome from their father. If the single X chromosome a male receives carries the mutated gene, there is no second, healthy copy to compensate, resulting in the full expression of the disorder. A male cannot pass the X-linked trait to his sons because he only contributes the Y chromosome to them.
Females, by contrast, inherit one X chromosome from each parent, giving them a “backup” copy. If a female inherits one mutated X chromosome, the healthy gene on her other X chromosome usually ensures she produces enough clotting factor to prevent severe bleeding symptoms. Such a female is referred to as a carrier because she carries the gene mutation and can pass it on. If a father has hemophilia, all of his daughters will inherit his affected X chromosome, making them obligate carriers.
Hemophilia A and B: Specific Genes and Factor Deficiencies
Hemophilia is not a single disease but a group of disorders defined by the specific clotting factor that is deficient. The two primary types, Hemophilia A and Hemophilia B, account for the vast majority of cases. Hemophilia A is the most common form, occurring in approximately 1 in 5,000 male births worldwide, and it is caused by a deficiency in Clotting Factor VIII (Factor 8). Mutations in the F8 gene lead to the body either making too little of Factor VIII or producing a non-functional version of the protein.
Hemophilia B, sometimes called Christmas disease, is less common, affecting about 1 in 20,000 newborn males. This type is due to a deficiency in Clotting Factor IX (Factor 9), which is governed by the F9 gene. Hemophilia C is distinct from the A and B types; it involves a deficiency of Factor XI and is caused by a mutation in the F11 gene. Since the F11 gene is located on a non-sex chromosome, Hemophilia C is inherited in an autosomal pattern and affects males and females equally.
Understanding Genetic Risk and Carrier Status
Understanding the inheritance pattern allows for the calculation of genetic risk, which is a significant part of family planning for those with a history of hemophilia. When a mother is a carrier and the father is unaffected, each of their children faces specific, independent risks. For every pregnancy, there is a 50% chance the mother will pass the affected X chromosome to the child. If the child is a son, there is a 50% chance he will inherit the affected gene and have hemophilia, and a 50% chance he will be unaffected. If the child is a daughter, there is a 50% chance she will be a carrier, inheriting the affected gene, and a 50% chance she will be neither affected nor a carrier.
Genetic counseling and testing are available to individuals who have a family history of the disorder or those whose children are newly diagnosed. Carrier testing can accurately identify females who carry the gene mutation, which is more reliable than simply measuring factor levels. This information is helpful for making informed decisions about future pregnancies, and prenatal testing can also determine if a fetus has hemophilia. In about a third of all cases, hemophilia appears without any prior family history of the disorder. This can occur due to a de novo, or new, genetic mutation in the F8 or F9 gene in the affected individual, or in the egg or sperm cell of one of the parents.