The hemoglobinopathies, molecular disease mechanisms and diagnostics

Abstract

Hemoglobinopathies are the most common monogenic disorders in the world with an ever increasing global disease burden each year. As most hemoglobinopathies show recessive inheritance carriers are usually clinically silent. Programmes for preconception and antenatal carrier screening, with the option of prenatal diagnosis are considered beneficial in many endemic countries. With the development of genetic tools such as Array analysis and Next Generation Sequencing in addition to state of the art screening at the hematologic, biochemic and genetic level, have contributed to the discovery of an increasing number of rare rearrangements and novel factors influencing the disease severity over the recent years. This review summarizes the basic requirements for adequate carrier screening analysis, the importance of genotype-phenotype correlation and how this may lead to the unrevealing exceptional interactions causing a clinically more severe phenotype in otherwise asymptomatic carriers. A special group of patients are β-thalassemia carriers presenting with features of β-thalassemia intermedia of various clinical severity. The disease mechanisms may involve duplicated α-globin genes, mosaic partial Uniparental Isodisomy of chromosome 11p15.4 where the HBB gene is located or haploinsufficiency of a non-linked gene SUPT5H on chromosome 19q, first described in two Dutch families with β-thalassemia trait without variants in the HBB gene.

The Relevance of β-Thalassemia Heterozygosity in Pediatric Clinical Practice: Croatian Experience

“…Carriers are frequently unaware of their disorder. As a rule, thalassemia trait is identified during the screening because of an affected family member, or rarely incidentally during routine laboratory analysis, e.g., HBA1c values in diabetic patients [35]. Molecular analysis is the only definitive way to diagnose heterozygous thalassemia and can be helpful in qualifying which HBB variant families harbor.…”

Bone Health Impairment in Patients with Hemoglobinopathies: From Biological Bases to New Possible Therapeutic Strategies

“…Hemoglobinopathies are the most common monogenic diseases worldwide which are characterized by altered hemoglobin synthesis [ 1 ]. Hemoglobin is a tetrameric protein present in erythrocytes involved in oxygen transport in the human body.…”

“…DNA variants in these genes are responsible for the onset of hemoglobinopathies. Hemoglobinopathies can be determined by an alteration of α- or β-globin synthesis (determining the onset of α- and β-thalassemia syndromes, respectively), or by hemoglobin structural impairment (resulting in the onset of several diseases such as sickle cell disease (SCD), hemolytic anemia, polycythemia, or erythrocytosis) [ 1 , 2 , 3 ].…”

SMPD1 gene variants in patients with β-Thalassemia major

“…Similarly, Niemann-Pick disease (NPD) is a common glycogen storage disease in Turkey [ 2 ]. Both diseases are autosomal recessive conditions with similar clinical presentations, including anemia, splenomegaly, and skeletal involvement [ 3 – 6 ]. In addition to these clinical and laboratory similarities, the genes affected in both diseases are located on the 11th chromosome [ 7 – 9 ].…”