Molecular basis of non-deletional HPFH in Thailand and identification of two novel mutations at the binding sites of CCAAT and GATA-1 transcription factors

High Hb F determinants are genetic defects associated with increased expression of hemoglobin F in adult life, classified as deletional and non-deletional forms. We report the first description of non-deletional hereditary persistence of fetal hemoglobin (HFPH) in Thailand. Study was done on 388 subjects suspected of non-deletional HPFH with elevated Hb F expression. Mutations in the (G)γ- and (A)γ-globin genes were examined by DNA analysis and rapid diagnosis of HPFH mutations were developed by PCR-based methods. Twenty subjects with five different mutations were identified including three known mutations, − 202 (A)γ (C>T) (n = 3), − 196 (A)γ (C>T) (n = 3), and − 158 (A)γ (C>T) (n = 12), and two novel mutations, − 117 (A)γ (G>C) (n = 1) and − 530 (G)γ (A>G) (n = 1). Interaction of the − 117 (A)γ (G>C) and Hb E (HBB:c.79G>A) resulted in elevation of Hb F to the level of 13.5%. Two plain heterozygous subjects with − 530 (G)γ (A>G) had marginally elevated Hb F with 1.9% and 3.0%, whereas the proband with homozygous − 530 (G)γ (A>G) had elevated Hb F of 11.5%. Functional prediction indicated that the − 117 (A)γ (G>C) and − 530 (G)γ (A>G) mutations dramatically alter the binding of transcription factors to respective γ-globin gene promotors, especially the CCAAT and GATA-1 transcription factors. Diverse heterogeneity of non-deletional HFPH with both known and new mutations, and complex interactions of them with other forms of thalassemia are encountered in Thai population.