εγ-Thalassemia, a New Hemoglobinopathy Category

Area of Science:

• Genetics and Molecular Biology
• Hematology
• Medical Diagnostics

Background:

• Large β-globin gene cluster deletions cause diverse phenotypes, including anemias and altered hemoglobin levels.
• ϵγδβ-thalassemias, lacking the locus control region (LCR), cause severe transient anemia but normal newborn screening (NBS) and Hb A2.
• A novel deletion of ϵ, Aγ, Gγ, and ψβ loci with intact LCR, δ-, and β-regions was identified in a family.

Purpose of the Study:

• To report a novel deletion within the β-globin gene cluster.
• To characterize the distinct phenotype associated with this deletion, termed ϵγ-thalassemia.
• To improve diagnostic approaches and genetic counseling for this newly identified hemoglobinopathy.

Main Methods:

• Utilized capillary electrophoresis (CE), high-performance liquid chromatography (HPLC), and DNA sequencing.
• Employed multiplex ligation-dependent probe amplification (MLPA), gap-polymerase chain reaction (gap-PCR), and long-read sequencing (LRS).
• Analyzed newborn screening (NBS) results and hemoglobin (Hb) levels.

Main Results:

• Newborn screening showed an Hb A > Hb F pattern in affected twins.
• Increased Hb A2 levels were observed without microcytosis or severe neonatal anemia.
• MLPA, LRS, and gap-PCR confirmed a 32,599 base pair deletion spanning ϵ (HBE1) through ψβ (HBBP1) loci.

Conclusions:

• A novel ϵγ-thalassemia with a distinct phenotype (increased Hb A2 without microcytosis) has been identified.
• This condition differs from severe ϵγδβ-thalassemia and requires specific diagnostic considerations.
• Recognition of this hemoglobinopathy category will enhance genetic counseling and diagnostic strategies.