εγ-Thalassemia, a New Hemoglobinopathy Category

Background Large beta-globin gene cluster deletions (hereditary persistence of fetal hemoglobin [Hb] or beta-, delta beta-, gamma delta beta-, and epsilon gamma delta beta-thalassemia), are associated with widely disparate phenotypes, including variable degrees of microcytic anemia and Hb F levels. When present, increased Hb A2 is used as a surrogate marker for beta-thalassemia. Notably, epsilon gamma delta beta-thalassemias lack the essential regulatory locus control region (LCR) and cause severe transient perinatal anemia but normal newborn screen (NBS) results and Hb A2 levels. Herein, we report a novel deletion of the epsilon, (A)gamma, (G)gamma, and psi beta loci with intact LCR, delta-, and beta-regions in 2 women and newborn twins. Methods Capillary electrophoresis (CE), high-performance liquid chromatography (HPLC), DNA sequencing, multiplex ligation-dependent probe amplification (MLPA), gap-polymerase chain reaction (gap-PCR), and long-read sequencing (LRS) were performed. Results NBS showed an Hb A > Hb F pattern for both twins. At 20 months, Hb A(2) was increased similarly to that in the mother and an unrelated woman. Unexplained microcytosis was absent and the twins lacked severe neonatal anemia. MLPA, LRS, and gap-PCR confirmed a 32 599 base pair deletion of epsilon (HBE1) through psi beta (HBBP1) loci. Conclusions This deletion represents a hemoglobinopathy category with a distinct phenotype that has not been previously described, an epsilon gamma-thalassemia. Both the NBS Hb A > F pattern and the subsequent increased Hb A(2) without microcytosis are unusual. A similar deletion should be considered when this pattern is encountered and appropriate test methods selected for detection. Knowledge of the clinical impact of this new category will improve genetic counselling, with distinction from the severe transient anemia associated with epsilon gamma delta beta-thalassemia.