Modifier genes in Mendelian disorders: the example of hemoglobin disorders

Abstract

The disorders of hemoglobin, including sickle cell disease (SCD) and β-thalassemia, are the most common "Mendelian" genetic diseases in the world. Numerous studies have demonstrated the complexity in making genotype-phenotype correlations in both SCD and β-thalassemia. Indeed, patients with exactly the same set of pathogenic globin mutations can have dramatically variable clinical courses. We discuss natural history studies that have attempted to delineate the factors responsible for the variability among the numerous clinical complications noted in these diseases. We then discuss, in depth, two well characterized ameliorating factors in the β-hemoglobin disorders, concomitant α-thalassemia, and elevated levels of fetal hemoglobin (HbF). We use the study of HbF regulation to illustrate how important insights into the genetic modifiers in Mendelian diseases can be achieved through the study of such factors. We finally go on to discuss future avenues of research that may allow us to gain further insight into the poorly understood clinical heterogeneity of this fascinating set of common genetic diseases.

Gene-centric association study of acute chest syndrome and painful crisis in sickle cell disease patients

“…4,5 Two nonenvironmental factors, high fetal hemoglobin (HbF) levels and concomitant a-thalassemia, also correlate with reduced morbidity and mortality in SCD. 6 The identification of additional disease-severity modifiers may yield novel insights into SCD pathophysiology. A genetic association study may improve understanding of SCD clinical heterogeneity because it attempts to correlate DNA sequence variants with SCDspecific complications or relevant clinical variables (eg, HbF).…”

Hydroxyurea responsiveness in -thalassemic patients is determined by the stress response adaptation of erythroid progenitors and their differentiation propensity

“…52 Expression levels of SOX6 are approximately 3.5-fold higher in R-HEPs compared to NR-HEPs, whereas expression of SOX4 was slightly less (Online Supplementary Figure S3D and Online Supplementary Table S3). No significant differences were seen in BCL11A expression between the two groups.…”

-Thalassemia Intermedia: A Clinical Perspective

“…There are several genes involved in modifying the gchain response, some that are encoded in the bglobin gene cluster, others that are on different chromosomes ( Fig. 1) (Sankaran et al 2010 related to globin chain production but that may have an important effect on the complications of the disease (Weatherall 2004).…”