Hemophilia is a genetic bleeding disorder where the blood does not clot properly due to a deficiency in specific proteins known as clotting factors. This deficiency leads to prolonged bleeding after injury, and in severe cases, spontaneous internal bleeding, particularly into the joints and muscles. The underlying cause is a mutation in the genes that provide the instructions for making these necessary clotting proteins. Understanding the genetic location of the affected genes provides insight into how the condition is passed down through families.
The X Chromosome Connection
The genes responsible for the two most common forms of the disorder, Hemophilia A and Hemophilia B, are located on the X chromosome. Hemophilia A, the most prevalent type, results from a defect in the F8 gene (Factor VIII). Hemophilia B is caused by a defect in the F9 gene (Factor IX). Because both genes are situated on the X chromosome, these conditions are categorized as X-linked recessive disorders.
The location of these genes explains the difference in prevalence between the sexes. Males possess one X and one Y chromosome (XY), while females possess two X chromosomes (XX). Since the Y chromosome lacks these clotting factor genes, a male who inherits a defective F8 or F9 gene on his single X chromosome will develop the disorder. Females usually have a second, healthy copy of the gene on their other X chromosome, which can compensate for the defective one.
Patterns of X-Linked Inheritance
The pattern of X-linked recessive inheritance dictates that males are far more likely to be affected by Hemophilia A or B. A male inherits his X chromosome directly from his mother, meaning he can only inherit the defective gene from her. If a mother is a carrier—meaning she has one normal and one mutated X chromosome—there is a 50% chance her son will inherit the affected chromosome and have hemophilia.
Females are typically carriers and usually do not experience severe bleeding symptoms because the normal gene copy produces sufficient clotting factor. For a female to be fully affected, she must inherit two copies of the mutated gene, one from each parent, which is extremely rare. Carriers may still have lower factor levels, leading to mild bleeding issues such as heavy menstrual bleeding or prolonged bleeding after surgery. An affected father cannot pass the condition to his son because he only contributes the Y chromosome.
How Factor Genes Affect Blood Clotting
The F8 and F9 genes contain instructions for creating Factor VIII and Factor IX, proteins that play an interconnected role in the coagulation cascade (the process of forming a blood clot). Within this cascade, Factor VIII acts as a cofactor, partnering with Factor IX (an enzyme). Together, they form the tenase complex, which activates Factor X and drives the final stages of clot formation.
A mutation in either the F8 or F9 gene results in the body producing insufficient amounts of the corresponding clotting factor, or a factor that is dysfunctional. Without adequate Factor VIII or Factor IX, the coagulation cascade is interrupted at a critical step. This severely limits the body’s ability to produce fibrin, the protein mesh that forms a stable clot, leading directly to prolonged and uncontrolled bleeding.
Hemophilia Types and Their Locations
While Hemophilia A and Hemophilia B are linked to the X chromosome, Hemophilia C (Factor XI deficiency) follows a different genetic pattern. Hemophilia C is caused by a deficiency in Factor XI, which is coded for by the F11 gene. This gene is not located on a sex chromosome but is instead found on an autosome, specifically Chromosome 4.
The autosomal location of the F11 gene means Hemophilia C is inherited differently, typically following an autosomal recessive pattern. Unlike the X-linked forms, this type affects males and females with equal frequency. Hemophilia C is generally considered a milder bleeding disorder than Hemophilia A or B. Many individuals with the condition are only diagnosed after experiencing bleeding following surgery or trauma.