What Type of Mutation Is Hemophilia?

Hemophilia is a genetic disorder that affects the blood’s ability to clot, leading to prolonged bleeding even from minor injuries. It primarily occurs in two forms: hemophilia A, caused by mutations in the F8 gene, and hemophilia B, resulting from mutations in the F9 gene. Both types lead to deficiencies in essential clotting factors, making proper medical management crucial.

Understanding the genetic mechanisms behind hemophilia explains why the condition predominantly affects males and how different mutations contribute to disease severity.

X-Linked Recessive Pattern

Hemophilia follows an X-linked recessive inheritance pattern, meaning the genetic mutations responsible for the disorder are located on the X chromosome. Since males have only one X chromosome, a single defective copy of the F8 or F9 gene is sufficient to cause the condition. In contrast, females, with two X chromosomes, are typically carriers rather than affected individuals, though some may experience mild symptoms due to skewed X-chromosome inactivation.

A carrier mother has a 50% chance of passing the mutation to her sons, who may develop hemophilia, and a 50% chance of passing it to her daughters, who may become carriers. Fathers with hemophilia cannot pass the condition to their sons but will pass the mutated X chromosome to all daughters, making them carriers.

Disease severity can vary due to additional genetic and epigenetic factors. Some female carriers may have mild bleeding tendencies if the functional X chromosome is preferentially inactivated in a significant proportion of their cells. This phenomenon, known as lyonization, has been observed in some carriers who exhibit clotting factor levels low enough to experience symptoms. Genetic counseling helps families navigate these inheritance dynamics.

Factor VIII And Factor IX Gene Alterations

Hemophilia A and B result from mutations in the F8 and F9 genes, which encode clotting factors VIII and IX, respectively. These genes are located on the X chromosome, with F8 spanning approximately 186 kilobases at Xq28 and F9 covering around 34 kilobases at Xq27.1. The structural complexity of F8, which contains numerous repetitive DNA sequences, makes it particularly susceptible to mutations, while F9, though smaller, also exhibits sequence variability that influences disease severity.

Mutations in these genes lead to deficient or dysfunctional clotting factors, impairing the coagulation cascade and causing prolonged bleeding. The severity of hemophilia correlates with the level of clotting factor deficiency: severe cases have factor levels below 1% of normal, moderate cases range from 1% to 5%, and mild cases fall between 5% and 40%.

One of the most common mutations in severe hemophilia A is the intron 22 inversion, which accounts for nearly 45% of cases. This mutation results from homologous recombination between repetitive sequences, disrupting F8 transcription. A similar but less frequent inversion in intron 1 contributes to 2-5% of severe cases. In hemophilia B, missense mutations are the predominant cause, with certain variants—such as p.Arg338Leu—associated with milder disease due to partial retention of factor IX activity.

Types Of Genetic Changes

The mutations responsible for hemophilia A and B vary in type and severity, affecting clotting factor production and function in different ways. These genetic alterations range from single-nucleotide changes to large-scale deletions and inversions, each influencing disease severity and treatment strategies.

Point Mutations

Point mutations, involving a single nucleotide substitution, are among the most common genetic changes in hemophilia, particularly in F9. These mutations can be classified as missense, nonsense, or splice-site mutations. Missense mutations result in an amino acid substitution, which may alter protein folding or enzymatic activity. For example, the p.Arg338Leu mutation in F9 leads to a milder form of hemophilia B due to partial retention of factor IX function.

Nonsense mutations introduce a premature stop codon, leading to truncated, nonfunctional proteins and typically causing severe disease. Splice-site mutations disrupt normal RNA processing, potentially leading to exon skipping or aberrant transcripts. Certain splice-site mutations in F8 can result in variable disease severity, depending on whether residual factor VIII is produced.

Inversions

Inversions are a major cause of severe hemophilia A, particularly the intron 22 inversion, which accounts for nearly half of all severe cases. This mutation occurs due to homologous recombination between repetitive sequences, flipping a segment of DNA and disrupting F8 transcription. A similar inversion in intron 1 is responsible for 2-5% of severe cases. These structural rearrangements prevent the production of functional factor VIII. Genetic testing for these inversions is a standard diagnostic approach for severe hemophilia A.

Large Deletions

Large deletions, which remove entire exons or even the entire F8 or F9 gene, are less common but typically result in severe hemophilia. These deletions eliminate the ability to produce functional clotting factors, leading to undetectable levels of factor VIII or IX. In hemophilia A, deletions spanning multiple exons are associated with a higher risk of developing inhibitors—neutralizing antibodies that complicate treatment. In hemophilia B, complete gene deletions are rare but result in severe disease with no detectable factor IX activity. Advances in next-generation sequencing and multiplex ligation-dependent probe amplification (MLPA) have improved the detection of these deletions, allowing for more precise genetic diagnosis.

Rare Spontaneous Mutation Occurrence

While hemophilia is primarily inherited, a significant proportion of cases arise from spontaneous mutations with no prior family history. These de novo mutations originate during gametogenesis or early embryonic development. Approximately 30% of hemophilia A and 20% of hemophilia B cases result from such spontaneous alterations.

Spontaneous mutations can take various forms, including point mutations, large deletions, and inversions. In hemophilia A, de novo intron 22 inversions frequently cause severe disease due to the gene’s susceptibility to recombination errors. In hemophilia B, missense mutations commonly arise sporadically, leading to varying disease severities. Advanced genetic sequencing has pinpointed the origins of these mutations, often tracing them to errors during DNA replication or repair mechanisms.