Reduced F8 activity is virtually diagnostic of HA provided VWD and specimen artifact have been excluded. Rare instances of other genetic disorders that can have low F8 activity include VWD type 2N (see section on VWD) and rare combined deficiencies of F5 and F8. The latter occurs as a result of mutations in ERGIC53, which encodes a protein necessary for efficient transport of F5 and F8 from the endoplasmic reticulum to the Golgi apparatus. F5 and F8 levels are typically in the 10% to 15% range. Molecular genetic testing is available only on a research basis.11
Detection of the presence of a mutation determines the genotype of the proband and can be used to confirm the carrier status of at-risk females. Certain well-defined mutations (e.g., inversions, deletions, insertions, splice junction mutations, and nonsense mutations) have obviously deleterious effects. Determining the deleterious nature of previously uncharacterized missense mutations poses a challenge. However, such a mutation in hemizygous genes (F8 and F9) and absence of additional mutations provide reasonable evidence of the effect of the mutation on the function of the protein. Other criteria typically considered in predicting the effect of a missense mutation include analysis of the degree of conservation of the respective residue among other species and presence of a similar mutation in other patients. The best evidence of the deleterious nature of a missense mutation is in vitro confirmation of its effect on protein function.
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