First report of Hb A2-NYU (HBD:c.39T>A) in the Hellenic population.

We report the first heterozygous case of Hb A(2)-NYU (HBD:c.39T>A) in the Hellenic population. The proband, an adult female from the island of Crete, Greece, was identified during routine family screening. DEAE chromatography of the index case revealed a minor hemoglobin (Hb) fraction preceding the elution of the wild-type Hb A(2). DNA sequencing of the entire HBD gene coding regions indicated that the index case was heterozygous for the rare variant Hb A(2)-NYU. Family studies indicated that this Hb variant was inherited from the mother. This finding underlines the vast genetic heterogeneity of the HBD gene in the Hellenic population.

The Hellenic type of nondeletional hereditary persistence of fetal hemoglobin results from a novel mutation (g.-109G>T) in the HBG2 gene promoter.

Nondeletional hereditary persistence of fetal hemoglobin (nd-HPFH), a rare hereditary condition resulting in elevated levels of fetal hemoglobin (Hb F) in adults, is associated with promoter mutations in the human fetal globin (HBG1 and HBG2) genes. In this paper, we report a novel type of nd-HPFH due to a HBG2 gene promoter mutation (HBG2:g.-109G>T). This mutation, located at the 3' end of the HBG2 distal CCAAT box, was initially identified in an adult female subject of Central Greek origin and results in elevated Hb F levels (4.1%) and significantly increased Ggamma-globin chain production (79.2%). Family studies and DNA analysis revealed that the HBG2:g.-109G>T mutation is also found in the family members in compound heterozygosity with the HBG2:g.-158C>T single nucleotide polymorphism or the silent HBB:g.-101C>T beta-thalassemia mutation, resulting in the latter case in significantly elevated Hb F levels (14.3%). Electrophoretic mobility shift analysis revealed that the HBG2:g.-109G>T mutation abolishes a transcription factor binding site, consistent with previous observations using DNA footprinting analysis, suggesting that guanine at position HBG2/1:g.-109 is critical for NF-E3 binding. These data suggest that the HBG2:g-109G>T mutation has a functional role in increasing HBG2 transcription and is responsible for the HPFH phenotype observed in our index cases.