The Genetic Link to Hemophilia: New Insights from a Large Pediatric Study

If you or a loved one lives with hemophilia, you know how important it is to understand the root cause of this rare bleeding disorder. A recent study from the PedNet Registry (a European network of pediatric hemophilia centers) offers fresh clues about the genetic changes that cause hemophilia A and B—and how these findings could improve care for patients and families. Here’s what you need to know.

What You’ll Learn

This study dives deep into the F8 (factor VIII) and F9 (factor IX) genes—where mutations cause hemophilia A and B, respectively. Researchers analyzed genetic data from over 1,900 children with hemophilia and compared their results to existing databases. The goal? To create a more complete picture of how genetic changes drive hemophilia—information that could help with diagnosis, family planning, and even future treatments.

A Quick Look at Hemophilia

Hemophilia is a rare genetic disorder that impairs blood clotting. People with hemophilia A lack enough factor VIII, a protein that helps blood clot. Those with hemophilia B (also called Christmas disease) lack factor IX. Without these factors, even minor injuries can lead to prolonged bleeding, which can be dangerous if it affects vital organs like the brain or joints.

Most cases of hemophilia are inherited: the faulty gene is passed from a mother (who carries the mutation) to her son. However, about 30% of cases are “sporadic”—meaning the mutation occurs randomly, with no family history.

Why Genetic Discoveries Matter for Hemophilia

Hemophilia is a genetic disease, so understanding the specific mutations in the F8 or F9 genes is key to:

• Accurate diagnosis: Genetic testing can confirm hemophilia even in mild cases where factor levels are borderline.
• Family planning: Knowing if a mutation runs in the family helps parents make informed decisions about having children.
• Targeted treatments: New therapies (like gene therapy) work by fixing or replacing the faulty gene—so knowing the exact mutation is critical for personalized care.

What the Study Found About Hemophilia Genes

The PedNet study is unique because it’s population-based—meaning it includes all children with hemophilia born in participating countries since 2000, not just select cases. This makes its data more reliable than existing databases, which often rely on voluntary reporting (and can miss rare or mild cases). Here are the key findings:

For Hemophilia A (F8 Gene)

• Severe hemophilia A: 52% of kids had an intron 22 inversion—a common genetic “break” in the F8 gene that stops it from making functional factor VIII. This matches what doctors already know, but the study confirms it’s the most frequent cause of severe disease.
• Non-severe hemophilia A (mild/moderate): Almost all cases (91–95%) were caused by missense mutations—small changes in the F8 gene that make factor VIII less effective. These mutations were often in specific parts of the gene (like the A2 domain for mild cases), which may explain why symptoms vary.

For Hemophilia B (F9 Gene)

• Severe hemophilia B: 48% of kids had missense mutations, followed by nonsense mutations (21%)—changes that stop the F9 gene from making any factor IX.
• Non-severe hemophilia B: 86% of cases were missense mutations, with differences in where the mutations occurred (e.g., more in the EGF1 domain for mild cases).

Comparing to Existing Databases

The study also looked at two major hemophilia databases (EAHAD and CHAMP/CHBMP) and found that PedNet’s data was more complete. For example:

• Existing databases overrepresented missense mutations in severe hemophilia B (68% vs. 48% in PedNet).
• PedNet included all types of mutations (like inversions), while some databases missed these common causes.

This matters because incomplete data can lead to misdiagnosis or missed opportunities for targeted care.

What This Means for Patients and Families

1. More Accurate Diagnosis

PedNet’s comprehensive data can help doctors better identify the specific mutation causing a child’s hemophilia—even in mild cases where factor levels are hard to interpret. This is especially important for kids with no family history (sporadic cases).

2. Better Genetic Counseling

The study found that missense mutations were less common in sporadic severe hemophilia A (10% vs. 17% in familial cases). This could help counselors explain risk to families: if a child has a sporadic case, the chance of a sibling inheriting the mutation is lower.

3. Future Treatments

Knowing exactly which part of the F8 or F9 gene is mutated helps researchers develop targeted therapies. For example, gene therapy for hemophilia A often targets the intron 22 inversion—so this study’s confirmation of its frequency helps prioritize research.

4. Understanding Symptom Variation

The study showed that where a mutation occurs in the F8 or F9 gene affects how severe hemophilia is. For example, missense mutations in the A2 domain of F8 are more likely to cause mild hemophilia A. This explains why two people with the same “type” of hemophilia can have very different symptoms.

Important Things to Remember

• Not all hemophilia is caused by these mutations: The study found that 2% of kids with hemophilia A and 1% with hemophilia B had no identifiable mutation in F8 or F9. This could be due to rare genetic changes or other factors.
• Genetic testing is complex: Interpreting mutations requires a specialist (like a genetic counselor or hematologist). Always discuss results with a professional.
• This is just one study: While PedNet’s data is robust, more research is needed to confirm these findings in larger, more diverse populations.

Key Points to Remember

• The PedNet study is the largest population-based analysis of hemophilia genetics to date.
• Intron 22 inversions are the most common cause of severe hemophilia A (52% of cases).
• Missense mutations are the main cause of mild/moderate hemophilia (91–95% for A; 86% for B).
• PedNet’s data is more complete than existing databases, which can improve diagnosis and care.

Talk to Your Doctor or Genetic Counselor

If you or your child has hemophilia, ask your doctor about genetic testing. This study’s findings can help you:

• Understand the specific cause of your hemophilia.
• Discuss family risk with a genetic counselor.
• Learn about new treatments that target your mutation.

Remember: You’re not alone. Hemophilia care has come a long way, and genetic research is opening doors to even better options.

This article is based on a study published in Research and Practice in Thrombosis and Haemostasis (2023) by the PedNet Study Group. For more details, ask your doctor or visit the National Library of Medicine’s PubMed Central (PMC9926204).