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Background: Deletions in the beta-globin cluster causing thalassaemia and hereditary persistence of fetal haemoglobin (HPFH) are uncommon and difficult to detect. Data in Chinese are very scarce., Aims: To use a recently available technique to investigate the frequencies and nature of beta-globin cluster deletions in Chinese., Methods: 106 subjects with phenotypes of thalassaemia or HPFH and suspected to have deletions in the beta-globin cluster were studied. A commercially available kit employing multiplex ligation-dependent probe amplification (MLPA) was used to screen for deletions. Gap PCR and direct nucleotide sequencing were used to characterise deletions detected., Results: 17 deletions in the beta-globin cluster were found in 17 patients: 8 of Chinese ((A)gammadeltabeta)(0) thalassaemia, 7 of Southeast Asian (Vietnamese) deletion and 2 of Thai ((A)gammadeltabeta)(0) thalassaemia. The only type of deletion detected in deltabeta-thalassaemia was Chinese ((A)gammadeltabeta)(0) thalassaemia. The deletional form of HPFH was rarely seen in only 1 case of Thai ((A)gammadeltabeta)(0) thalassaemia. Deletions presenting as beta-thalassaemia trait and raised HbF were all of the Southeast Asian (Vietnamese) deletion type. When these deletions were co-inherited with classical beta-thalassaemia mutations in compound heterozygous states, the phenotypes could be very variable., Conclusions: In the Chinese population, there are only relatively few types of deletions seen in the beta-globin cluster. MLPA is a fast and effective way of screening for these deletions. Characterisation of these deletions allows the development of simpler and more specific PCR-based tests for routine diagnostic use. Accurate prediction of phenotype is not always feasible. The molecular defects in many cases of HPFH still await discovery.

Enhanced fetal hemoglobin (Hb F) production can partially compensate for the lack of adult hemoglobin (Hb A) in patients with beta-thalassemia major or intermedia, and ameliorate the clinical severity of these diseases. To further elucidate factors governing Hb F levels, we evaluated demographic, clinical, laboratory, and genetic characteristics in 241 unrelated adult beta-thalassemia carriers in Hong Kong. They had wide variations in Hb F and F-cell numbers skewing toward higher levels. Individuals who coinherited the Xmn IT-allele in the (G)gamma-globin gene promoter had higher Hb F and more F-cells compared with those lacking the Xmn I T-allele. However, both groups exhibited a similarly wide spread of Hb F and F-cells. The correlation of Hb F and F-cells corresponded well to both linear and exponential models, suggesting multiple mechanisms for Hb F augmentation. The heritabilities of Hb F and F-cells were calculated in 66 families (111 parents who were beta-thalassemia carriers and 82 asymptomatic offspring) to be 0.7 to 0.9. The Xmn I polymorphism accounted for 9% of the Hb F and 13% of the F-cell heritabilities. These results suggest that these family members are well suited for genome wide association studies that will identify genetic loci regulating Hb F production, and likely novel pharmacological targets for reactivating Hb F production in adults., (Copyright 2008 Wiley-Liss, Inc.)

An extended family with three individuals affected by two different forms of double heterozygosity for beta-thalassemia and Hb New York is reported. Double heterozygosity of Hb New York [beta 113 GTG-->GAG; VAL-->GLU] and beta degrees codon 17 was detected in a fetus following prenatal screening for thalassemia. The father and a paternal aunt were also found to be heterozygous for Hb New York and beta degrees IVSII-654. Both adults had clinical and hematological features consistent with beta-thalassemia trait. The affected child was followed up after birth and manifested the typical course of a thalassemia trait, with no signs of organomegaly or overt hemolysis. Observations strongly suggest that double heterozygosity of Hb New York and beta degrees thalassemia has mild, if any, clinical symptoms, and is not an indication of therapeutic abortion when detected antenatally.

In this report we examine the (AC)n(AT)xTy motif residing -530 bp 5' upstream of the beta-globin gene in Chinese thalassaemic patients. This motif is a putative binding site for a repressor protein, termed beta protein 1 (BP1) (Berg et al., Nucleic Acids Res 1989;17:8833-8852). Variations in the (AC)n(AT)xTy repeats affect the binding affinity of BP1, thereby altering the expression of the beta-globin gene. Eight different configurations of this repeat motif are identified in our population of Chinese beta-thalassaemia patients. A (AC)3(AT)7T5 motif was identified among these thalassaemia patients and its influence in beta-globin gene expression was studied using stable transfection assay in murine erythroleukemia (MEL) cells. Our data demonstrated that the (AC)3(AT)7T5 motif has a moderately strong repressor effect on the expression of the cis-linked beta-globin gene. The high affinity of BP1 for this motif may result in the suppression of the transcription of the beta-globin gene (Berg et al., Am J Hematol 1991;36:42-47). We postulate that silencer elements in the beta-globin promoter play an important role in modifying the clinical presentation of the disease., ((c) 2006 Wiley-Liss, Inc.)

Two brothers from a Chinese family with beta-thalassemia intermedia who harbor both alpha- and beta-globin gene defects are described. They are both compound heterozygous for codons 41/42 (-CTTT) beta0-thalassemia and nt - 28 (A > G) beta(+)-thalassemia mutations together with concurrent (- -SEA) alpha-thalassemia (SEA) deletion. One sibling also harbors Hb Westmead, giving an unusual genotype of beta0/beta(+)-thalassemia and (- -SEA) alpha-thalassemia/Hb Westmead. With respect to the age at presentation and transfusion requirement, this subject shows a milder clinical phenotype than his brother, most probably explainable by the presence of Hb Westmead in addition to the SEA deletion, which causes a further amelioration of the alpha-chain excess and hence a less severe disease. For areas with high prevalence of both alpha- and beta-thalassemia mutations, their interactions should always be considered in genotype phenotype correlation. Moreover, routine laboratory diagnostic strategy for non-deletional alpha-globin gene mutations in the Chinese may need to include Hb Westmead, as it is a common alpha-globin gene mutation in our population apart from Hb Constant Spring and Hb Quong Sze.

Purpose: A program of cord blood stem cell (CBSC) transplants for patients with beta-thalassemia major was initiated in conjunction with the prenatal diagnostic service in 1994. Two patients who received HLA-matched related CBSC transplants with posttransplant fetal hemoglobin (HbF) expression are described and the literature is reviewed., Patients and Methods: After screening 12 pregnancies, matched sibling CBSC transplants were performed for 2 girls with beta-thalassemia major when they were 3.8 and 2.2 years old, respectively. Their HbF was assayed serially., Results: The nucleated cell counts/kg were 11.4 x 10(7) and 6.2 x 10(7), which engrafted on days 19 and 24, respectively. The children are now transfusion-independent at 3 years and 1.2 years posttransplant. Their HbF levels showed a rapid rise posttransplant and reached peak levels of 37.2% and 42.2% on day 83 and day 88, respectively. The HbF levels declined to 1.0% and 3.8% on day 581 and day 305, respectively. Nine other sibling CBSC transplants for thalassemias have been reported with an engraftment rate of approximately 50%. Graft rejection was related to insufficient CBSC number in one., Conclusions: HbF levels in patients with beta-thalassemia major after CBSC transplants could be influenced by many factors, including reactivation of HbF synthesis, intrinsic rate of Hb switching of CBSC, and mixed chimerism.