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4bases’ paper of the month – May 2023 – εγ-Thalassemia, a New Hemoglobinopathy Category

In this recently published article, a multidisciplinary group from the Mayo Clinic (Rochester, Minnesota) details the discovery of a new type of thalassemia, a genetic disorder affecting Hemoglobin (Hb) in red blood cells.

Hemoglobin is the carrier of oxygen from the lungs to the rest of the body and undergoes structural evolutions during development. In the embryo, the prevalent Hb structure is called ϵ (epsilon). It is progressively replaced by fetal Hb (Hb F, characterized by the γ subunit) after about 11 weeks of gestation. Then, a Fetal to Adult Hb switch occurs gradually between 4 and 12 months after birth. The final adult Hemoglobin is composed of 2 α and 2 β subunits.

Thalassemia is caused by deletions in the DNA sequences of Hemoglobin subunits. For example, β-thalassemia arises from deletions in the sequence of the β-globin cluster. But screening for hemoglobin defects in newborns’ blood samples is difficult because as mentioned, their blood composition is still evolving. Fortunately, the body is also able to mitigate thalassemia on its own by continuing to produce Fetal Hb. This adaptation related to significant deletions of β-genes is called Hereditary Persistence of Fetal Hemoglobin (HPFH).

Due to these physiological variations and the large array of possibly affected Hb subunits, Thalassemias encompass symptoms of varying gravity, such as anemia (lack of iron in the blood) and microcytosis (undersized red cells), leading to shortness of breath and weakness induced by insufficient oxygen transport.

At the genomic level, thalassemias are characterized by the absence of a DNA sequence called  LCR (Locus Control Region). The LCR enhances the expression of Hb subunits and is thus essential in healthy blood cells development.
Here, the newly reported disease type, ϵγ-thalassemia, presents a preserved LCR. This leads to an absence of microcytic anemia and to an overall asymptomatic phenotype even right after birth. This is in contrast to other rare thalassemia forms such as εγδβ, which resume after a couple of years but can still be life threatening at birth.

The rarity and benignity of the defect explain why its genotype is just being reported now. But despite being harmless, this discovery stresses the importance of correctly classifying thalassemia using efficient screening methods to ensure an appropriate medical response. In this regard, 4bases Thalassemia panel for α and β globins provides insight into blood samples by interrogating them directly at the DNA level.

Jennifer L Oliveira, Christineil H Thompson, Siva Arumugam Saravanaperumal, Tejaswi Koganti, Garrett Jenkinson, Molly S Hein, Mira A Kohorst, Linda Hasadsri, Phuong L Nguyen, Dietrich Matern, Benjamin R Kipp, Eric W Klee, Eric D Wieben, James D Hoyer, Aruna Rangan, εγ-Thalassemia, a New Hemoglobinopathy Category, Clinical Chemistry, 2023; doi.org/10.1093/clinchem/hvad038


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