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 Gγ- and Aγ-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 Aγ (C>T) (n = 3), - 196 Aγ (C>T) (n = 3), and - 158 Aγ (C>T) (n = 12), and two novel mutations, - 117 Aγ (G>C) (n = 1) and - 530 Gγ (A>G) (n = 1). Interaction of the - 117 Aγ (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 Gγ (A>G) had marginally elevated Hb F with 1.9% and 3.0%, whereas the proband with homozygous - 530 Gγ (A>G) had elevated Hb F of 11.5%. Functional prediction indicated that the - 117 Aγ (G>C) and - 530 Gγ (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.

Prevalence of Thalassemia among Newborns: A Re-visited after 20 Years of a Prevention and Control Program in Northeast Thailand.

BACKGROUND: To provide accurate prevalence information of thalassemia in northeast Thailand, authors performed thalassemia screening in newborns after 20 years implementation of a prevention and control program. METHODS: Study was done on 350 cord blood specimens collected consecutively at Maternal and Child Hospital, Regional Health Promotion Center 7, Khon Kaen, Thailand. All kinds of α- and ß-thalassemias were identified using combined hemoglobin (Hb) and DNA analyses. RESULTS: Among 350 newborns examined, subjects with thalassemia genes were identified in 184 (52.6%) cases with as many as 22 different genotypes. The most prevalent one was Hb E (39.1%). The incidence of 3.1% α0-thalassemia, 25.9% α+-thalassemia, 5.4% Hb Constant Spring and 1.4% of Hb Paksé were encountered. Heterozygous ß-thalassemia was found in 2 cases (0.6%). Hb capillary electrophoresis could demonstrate Hb E in all cases with Hb E and detected different levels of Hb Bart's for different α-thalassemia genotypes but not in all cases with α-thalassemia. No newborn with severe thalassemia diseases was encountered. CONCLUSION: This study reveals that α-thalassemia, ß-thalassemia, and Hb E carriers as well as complex thalassemia syndromes are still prevalence and indicates a need for continuing a prevention and control program in the region.