Hemophilia B, Factor IX Gene Mutation Screening
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Hemophilia B, factor IX deficiency, is an X-linked recessive bleeding disorder with an incidence of about 1 per 30,000 live male births. It occurs as a result of mutations in the factor IX (F9) gene. As many as one-third of hemophiliacs have no affected family members, reflecting a high mutation rate (ie, de novo mutations). Hemophilia B affects males; however, all male offspring from an affected male will be normal. Although all female offspring of affected males will be obligatory carriers, they rarely have symptomatic bleeding. In contrast, female offspring of female carriers of hemophilia B have a 50% chance of being carriers themselves and each male offspring has a 50% chance of being affected.
Based on factor IX activity, hemophilia B is classified as severe (factor IX activity <1%), moderate (factor IX activity > or =1%–<5%), or mild (factor IX activity > or =5%–40%). In males, a low factor IX activity level establishes the diagnosis of hemophilia B. However, the wide range of normal factor IX activity precludes an accurate assessment of carrier status in females, thus making molecular testing essential in assessment of carrier status.
Inhibitors to factor IX activity are estimated to occur in 5% to 8% of patients, much less than that of hemophilia A. Inhibitor risk correlates with genotype and typically occurs in patients with either partial or total deletions of the F9 gene or in certain nonsense mutations that result in no circulating factor IX:antigen. More recently, it has been observed that a subset of patients with such mutations may be at risk of experiencing anaphylactic reactions to the factor IX replacement therapy.
Indirect methods of determining carrier status by restriction fragment length polymorphism (RFLP) are available, but limited by the necessity of a detailed pedigree, DNA specimens volunteered from multiple members of the family, and an absolute requirement of an informative polymorphism that is associated with the defective gene. Even then, accuracy is <100%. The size and X-linked nature of the F9 gene facilitates direct mutation analysis, which requires DNA from only a limited number of family members and is nearly100% accurate. The apparently small gain in accuracy of carrier testing has enormous implications for the carriers.
Ascertaining the causative mutation in the F9 gene of patients with congenital hemophilia B (factor IX activity deficiency)
Carrier testing of females in whom the familial F9 genotype is unknown
The interpretive report will contain specimen information, assay information, background information, and conclusions based on the test results (ie, information about the mutation and carrier status).
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Special Coagulation Clinic/Laboratory and Medical Genetics consultations are available for DNA diagnosis cases and may be especially helpful in complex cases or in situations where the diagnosis is atypical or uncertain.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be issued which will include specimen information, assay information, background information, and conclusions based on the test results (ie, information about the mutation and carrier status).
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Yoshitake S, Schach BG, Foster DC, et al: Nucleotide sequence of the gene for human factor IX (antihemophilic factor B). Biochemistry 1985 July 2;24(14):3736-3750
2. Giannelli F, Green PM, Sommer SS, et al: Haemophilia B: database of point mutations and short additions and deletions. Eighth edition. Nucleic Acids Res 1998 Jan 1;26(1):265-268
3. Ketterling RP, Bottema CD, Phillips JA 3rd, et al: Evidence that descendants of three founders constitute about 25% of hemophilia B in the United States. Genomics 1991 Aug;10(4):1093-1096