A novel α0-thalassemia deletion in a Greek patient with HbH disease and β-thalassemia trait

Objectives: To determine the molecular basis in a Greek child suspected of having HbH disease and β-thalassemia trait. Methods: Standard hematology, Hb electrophoresis, and HPLC. Multiplex ligation-dependent probe amplification (MLPA), direct sequencing, and breakpoint characterization by NimbleGen fine-tiling array analysis. Results: The index patient showed a moderate microcytic hypochromic anemia with normal ZPP and elevated HbA2, indicative for β-thalassemia trait. However, the moderate microcytic hypochromic anemia along with the observation of HbH inclusions in occasional red blood cells suggested a coexisting α-thalassemia. Molecular analysis indicated that the propositus inherited the β+-thalassemia mutation IVS2-745 (c>g) and a novel α0-thalassemia deletion from the mother, and the common non-deletion α-thalassemia allele α2(−5nt)α from the father. The α0-thalassemia deletion, named - -BGS, is approximately 131.6 kb in length. It removes the major regulatory elements along with the functional α-globin genes but leaves the theta-gene intact. Conclusions: The compound interaction of a β-thalassemia defect along with a single functional α-globin gene is quite rare. Although patients with HbH/β-thal and simple HbH disease have comparable levels of Hb, the absence of free β-globin chains and thus detectable non-functional HbH means that in HbH/β-thal, the levels of functional Hb are higher, resulting in a better compensated functional anemia. Rare large deletions as the one described here remain undetected by gap-PCR in routine molecular screening. The introduction of MLPA as a diagnostic screening tool may improve laboratory diagnostics for these defects. The use of NimbleGen fine-tiling arrays may give additional information about the precise location of breakpoints.