Modifier Genes in the Haemoglobinopathies

Haemoglobinopathies, such as sickle cell disease (SCD) and thalassaemias, are prototypical single-gene disorders caused by lesions that affect the β-globin gene (SCD and β-thalassaemia) or α-globin gene (α-thalassaemia). Haemoglobinopathies are among the most common human genetic disorders, and patients having the same genotypes can have variable pattern of clinical expression related to environmental as well as genetic factors. Several modifier genes have been identified which are able to influence the severity of these diseases, so at phenotypic level haemoglobinopathies are considered multigenic diseases. It is possible that additional modifiers could be uncovered using genetic approaches but success will depend on large sample sizes of well-characterised patients with well-defined phenotypes. Improved understanding of the influence of modifier genes involved in modulating the complex pathophysiology of haemoglobinopathies may allow prediction of diseases’ phenotype and aid in management of the many complications of these diseases. Key Concepts: Haemoglobinopathies, such as sickle cell disease (SCD) and thalassaemias, are prototypical single-gene disorders caused by lesions that affect the β-globin gene (SCD and β-thalassaemia) or α-globin gene (α-thalassaemia). Patients having the same genotypes can have variable pattern of clinical expression related to environmental as well as genetic factors. The phenotypic variability of the disease is due, at primary level, to the heterogeneity of the causative mutation, especially for thalassaemia. Modifier genes are defined as inherited genetic variation that leads to a qualitative or quantitative difference in disease phenotype. Several modifier genes have been identified able to influence the severity of haemoglobinopathies, so at phenotypic level they are considered multigenic diseases. Alterations of other globin genes and the inheritance of different quantitative trait loci (QTLs) associated with the increase of fetal haemoglobin (HbF) production are the major genetic modifiers in haemoglobin diseases. Variations in the phenotype of some complications in patients with beta-thalassaemia and sickle cell anaemia may be affected by genetic variants. Keywords: haemoglobinopathies; modifier genes; fetal haemoglobin; QTLs; GWAS