Hereditary
anemias show considerable variation in their clinical presentation. In some cases, the causes of these variations are easily apparent. In
thalassemia (or in HbE/
thalassemia), genetic variation is primarily caused by the severity of the
thalassemia mutation. However, not uncommonly, there is variation unexplained by the
globin gene mutations themselves, which may be caused by genetic modifiers. In
sickle cell disease, the primary mutation is the same in all patients. Therefore, variations in disease severity generally are due to genetic modifiers. In most
genetic diseases involving
beta globin, the most clearcut influence on phenotype results from elevated
fetal hemoglobin levels. In addition,
alpha globin gene number can influence disease phenotype. In
thalassemia major or intermedia, reduction in the number of
alpha globin genes can ameliorate the disease phenotype; conversely, excess
alpha globin genes can convert
beta thalassemia trait to a clinical picture of
thalassemia intermedia. In
sickle cell disease, the number of
alpha globin genes has both ameliorating and exacerbating effects, depending on which disease manifestation is being examined. Unlinked genetic factors have substantial effects on the phenotype of hereditary
anemias, both on the
anemia and other disease manifestations. Recently, studies using genome-wide techniques, particularly studying QTLs causing elevated HbF, or affecting HbE/
thalassemia, have revealed other genetic elements whose mechanisms are under study. The elucidation of genetic modifiers will hopefully lead to more rational and effective management of these diseases.