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 haplo-insufficiency 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.

Keywords: haematology; haemoglobin; molecular diagnosis; sickle cell disease; thalassemia; β-thalassemia intermedia.

FIGURE 1

Schematic presentation of the different types of haemoglobin molecules synthesized during different stages of development. The graph shows the ontological expression of the α‐like and non‐α‐like‐globin genes pre‐ and postnatally and the steep change in γ‐ to β‐globin synthesis around birth.

FIGURE 2

Summary of duplications of the α‐globin gene locus on chromosome 16p13.3. The duplicated area is indicated as a black bar. The region of uncertainty when the duplication is not entirely mapped is indicated in white. The open lines indicate that the extend of the duplication is unknown. From the sequence data available a head‐to‐tail orientation was evident. The last duplication by Hu et al. (2016) was found to be integrated at position 94 054 bp, upstream of POLR3K.

FIGURE 3

Schematic presentation of the short arm of chromosome 11 with summary of partial Uniparental Iso‐Disomy (UPD) and segmental deletions of chromosome 11p (the scale is in Mb). The position of the HBB, H19 and IGF2 are indicated. The paternally inherited variant in the HBB gene is indicated with an asterisk. The blue bars indicate the segmental Uniparental isodisomic region of the paternal allele carrying the β⁰‐thalassemia variant, in orange the HbS variant detected by Swensen et al. in a boy with late‐onset sickle cell disease. The deletions of the maternally inherited allele are indicated as lines. Stippled lines indicate uncertainty in length. All patients show mosaicism for either UPD or deletions in the DNA derived from blood isolated when developing adult‐onset of β‐thalassemia intermedia or major.