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Medical aspects : Genetics/Immunology

Hospital Donostia"s Genetic Services

Genetic counseling is an educational and informative process designed to treat problems related to the appearance or risk of recurrence of a specific disorder within a family. In our case, this disorder is hemophilia.


1. Help inform people of their own well-being and that of their offspring.

2. Guarantee informed consent for carrying out genetic tests and explain the procedures used, being sure to include information about the following:

  • hemophilia, prognosis and therapy options
  • mode of transmission
  • hemophilia and carrier diagnostic tests and their reliability
  • carrier screening procedures
  • prenatal diagnosis, tests and risks for both the mother and fetus
  • information regarding test results
  • ways of terminating pregnancy and related future implications.

3. Teach hemophilic patients how to talk about their condition and how to inform family members about the hereditary risks. It is important these patients be supported in any decisions they make.

4. Provide couples and families with the opportunity to attend sessions organized by Hematology or the Hemophilia Association.

5. Find out how it was transmitted. Be sensitive when talking to people of different religious, cultural, social and personal backgrounds.

In summary, the family seeking treatment should know what the disease is, how it is treated, its mode of inheritance, the likelihood their offspring inherit it, error factors in risk calculation and diagnostic testing, etc. They should also be informed of alternatives that exist so they can choose the best treatment plan. Elaboration of a detailed family tree with reliable information is very important. Errors in diagnosis or genealogy information can be misleading when interpreting results.

About hemophilia

Hemophilia A and B are the most severe genetic bleeding disorders in humans, the former accounting for about 80% of all hemophilia cases. The incidence of hemophilia A is 1-2 out of every 10,000 live births, whereas that of hemophilia B is 2-4 out of every 100,000. It is estimated 1 in 5,000 women is a carrier in the general population. Hemophilia A results from a deficiency or abnormality in active clotting factor VIII (FVIII:C), a glucoprotein of low molecular weight that is responsible for coagulation. FVIII:C binds to a carrier molecule of high molecular weight known as von Willebrand factor (VIII:Ag). These two coagulation factors are normally found in equal quantities. While FVIII:C, whose deficiency causes hemophilia A, is coded by a gene linked to the X chromosome, FVIII:Ag, whose deficiency causes von Willebrand disease, is coded by an autosomal gene found on chromosome 12.

Hemophilia B, also known as Christmas disease, occurs when there is a shortage of or abnormality in a vitamin-K-dependent clotting factor known as factor IX (FIX). The social, economic and clinical-pathological importance of both hemophilia types is well known and their severity is related to blood levels of their respective deficient clotting factors. Levels between 0-1% is considered severe, whereby the patient experiences frequent and spontaneous bleeding episodes. Levels between 1-5% is generally classified as moderate, although in some cases clinical manifestations appear to be those of the severe type. Levels between 5-30% implies a less important shortage evidenced by mild to moderate bleeding. Although once considered fatal, factor replacement therapy using blood derivatives, FVIII or FIX concentrates, purified factors, etc. has proven to be an important advance in terms of life expectancy and quality of life. This serves as an example of the importance of genetic counseling, especially if we take into account that nowadays hemophilic males reach adulthood with minimal disabilities and often have children.

Heredity. Both are X -linked recessive disorders


  1. The sons of hemophilic fathers will neither have the disease nor pass it on to offspring.
  2. All daughters of hemophilic fathers will be carriers and run a 50% chance of having carrier daughters or affected sons.
  3. Sporadic cases, which occur approximately one-third of the time, can occur where a child born with hemophilia comes from a family that has no known history of bleeding disorders. It is estimated that the mother of a sporadic case has an 85-90% chance of being a carrier and initially a 42-45% chance of having affected sons or carrier daughters.
  4. The mother is a carrier if she has more than one affected son.
  5. If a hemophilic male marries a carrier female (a rare event unless they are blood-related), 50% of male offspring will be affected and the other 50% healthy, whereas 50% of female progeny will be affected and the remaining 50% carriers.
  6. Women only have the disease if their father is hemophilic and their mother is a carrier (an exceptional case) or if there is sex-chromosome anomaly, as in the case of Turner Syndrome (45X). 

Diagrams for points 1,2,3

Molecular basis

The factor VIII gene is 186Kb in size and found on the q28 region of the X chromosome. Its large size contributes to a strong likelihood of there randomly existing numerous mutations or alterations in the gene, which explains the heterogeneity of the clinical expression of hemophilia A. 40-45% of severe cases are due to intron 22 inversion of the gene resulting from homologous recombination between the intragenic and extragenic copies. Less frequent are the deletions or point mutations (single base substitutions), which widely differ from one family to the next.

The factor IX gene is 34Kb in size and found nearby in the q26 region of the X chromosome. Different sized deletions and point mutations are the molecular mechanisms responsible for the clinical expression of hemophilia B. Unlike intron 22 inversion in hemophilia A, there is no principal mutation in hemophilia B, giving rise to its largely heterogeneous nature. For both types of hemophilia, identifying the mutation in one family member allows for a simple prediction about the rest of the family members. Each gene has coding parts called EXONS and non-coding parts for proteins called INTRONS, which are spliced out by RNA. A DNA analysis can be one of the following:

  • Direct, for when the mutation is known. Offers reliable diagnosis.
  • Indirect or linkage, for when it is impossible to identify the mutation. A highly reliable, but probabilistic diagnosis. The intragenic or extragenic markers utilized include RFLP (restriction fragment length polymorphisms obtained after exposing the gene to different enzymes) and VTNR or minisatellites (regions of the genome characterized by a number of tandem repeats that vary from one individual to another). Because the degree of informativity of each polymorphism varies, results are improved by combining several of them.

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