The Masked Thalassemia: A Rare Case of a Patient with Normal HbA2 Levels, β-Thalassemia Pathogenic Variant (CD39 C>T), and a Novel δ-Globin Gene Deletion

Massimiliano Chetta,1 Annamaria Salamandra,1 Marina Tarsitano,1 Marcella D’Antonio,1 Elvira Sannino,1 Serena Torre,1 Carmina Fatigati,2 Silvia Costantini,2 Paola D’Ambrosio,1 Manuela Priolo,1 Paolo Ricchi2 1U.O.C Medical Genetics and Laboratory, A.O.R.N. A. Cardarelli Hospital’s, Naples, Italy; 2U.O.S.D. Malattie Rare del Globulo Rosso, A.O.R.N. A. Cardarelli Hospital’s, Naples, ItalyCorrespondence: Massimiliano Chetta, U.O.C Medical Genetics and Laboratory, A.O.R.N. A. Cardarelli Hospital’s, Naples, Italy, Email [email protected]: Thalassemia is a group of inherited blood disorders caused by defects in hemoglobin production, the protein that transports oxygen in red blood cells. These diseases are characterized by either diminished or missing production of one of the globin chains, which are often the alpha or beta chains that comprise hemoglobin. Diagnosis is based on a combination of laboratory tests, including hemoglobin electrophoresis, globin chain chromatography, and genetic analysis. However, diagnosis can become challenging when typical hematological features of thalassemia are not matched by expected biochemical findings. One such situation occurs when HbA2 levels appear normal despite a suspected β-thalassemia trait. This can happen when a β-globin gene variant is present alongside a δ-globin gene pathogenic variant, producing an atypical profile that may mask the true diagnosis. In this case report, we describe a patient carrying a heterozygous β-globin pathogenic variant (HBB c.118C>T; p.Gln40Ter, also known as codon 39) coexisting with a large novel 1.6 kb deletion in the delta-globin gene (HBD) that removes the first two exons. We discuss the diagnostic challenges and clinical implications associated with this rare genetic combination, emphasizing the critical role of comprehensive molecular testing in accurately identifying complex thalassemia cases. This report contributes to the literature by documenting a novel δ-globin deletion in combination with a β-thalassemia variant, providing valuable insights for clinicians and geneticists in the interpretation and management of atypical thalassemia profiles.Keywords: β-thalassemia, novel δ-globin deletion, normal HbA2, masked thalassemia, molecular diagnosis, next-generation sequencing