Hematologic Disorders: Hemochromatosis, Hemoglobinopathies, and Rh Incompatibility

Abstract

Hereditary hemochromatosis (HHC) is a disorder of iron metabolism and has been classified into six types having similar phenotypes but caused by mutations in different genes involved in the regulation of iron stores. Two allelic variants of the HFE gene, p.C282Y (c.845G>A) and p.H63D (c.187C>G), are significantly correlated with HHC, and most clinical studies have focused on these variants. Diagnosis of HHC is based on clinical, biochemical, histological, and molecular studies, specifically tests such as transferrin saturation, ferritin concentration, evaluation of iron stores by liver biopsy, and genotyping for p.C282Y and p.H63D mutations in HFE. Hemoglobinopathies are the most common single-gene diseases in the world. Approximately 5–7 % of the world’s population is a carrier for one of the hemoglobin disorders. Two copies of the alpha (α) globin genes are present (α1 and α2) on each chromosome 16. The beta and beta-like chains (e, Gγ, Aγ, and δ) are clustered on chromosome 11. The hemoglobinopathies are commonly divided into two broad categories: structural variants, and thalassemias that are characterized by reduced rates of production of α or β chains. Sickle hemoglobin results from a single nucleotide substitution (GAG→GTG) that changes codon 6 of the β-globin gene from a glutamic acid to a valine (Glu6Val). Homozygosity for this mutation causes sickle cell disease (SD), an autosomal recessive disorder. SD is a major cause of morbidity and mortality in Africa and in populations with individuals of African descent. The α-thalassemias are most commonly caused by deletions while the β-thalassemias are most likely due to single nucleotide substitutions or frameshift mutations. Single nucleotide changes causing either structural variants or thalassemias can be easily diagnosed by targeted mutation analysis or by sequencing. Gap-PCR or multiplex ligation dependent probe amplification assays are the common methods to detect deletions. The Rh antigen system is clinically important because antibodies to Rh antigens are involved in hemolytic transfusion reactions, autoimmune hemolytic anemia, and hemolytic disease of the fetus and newborn. The Rh antigens are expressed on proteins encoded by two distinct but highly homologous genes, RHD and RHCE, on chromosome 1p34.3-36.1. The D antigen is expressed from RHD and the C/c and E/e antigens are expressed from RHCE. Rh incompatibility cases require both phenotypic and genotypic testing of parental samples.