Genetic Basis and Genetic Modifiers of β-Thalassemia and Sickle Cell Disease

beta-thalassemia and sickle cell disease (SCD) are prototypical Mendelian single gene disorders, both caused by mutations affecting the adult beta-globin gene. Despite the apparent genetic simplicity, both disorders display a remarkable spectrum of phenotypic severity and share two major genetic modifiers-alpha-globin genotype and innate ability to produce fetal hemoglobin (HbF, alpha(2)gamma(2)). This article provides an overview of the genetic basis for SCD and beta-thalassemia, and genetic modifiers identified through phenotype correlation studies. Identification of the genetic variants modifying HbF production in combination with alpha-globin genotype provide some prediction of disease severity for beta-thalassemia and SCD but generation of a personalized genetic risk score to inform prognosis and guide management requires a larger panel of genetic modifiers yet to be discovered. Nonetheless, genetic studies have been successful in characterizing some of the key variants and pathways involved in HbF regulation, providing new therapeutic targets for HbF reactivation.