ARTICLES 305 Thalassemia Syndromes IntroductionA growing number of studies describe BCL11A as a major repressor of fetal hemoglobin (HbF) expression. These include the description of several single nucleotide polymorphisms (SNPs) located in the BCL11A gene and linked to HbF level, and thus, the severity of sickle cell disease and beta-thalassemia (bthal) 1-4 and the demonstration of the direct binding of this transcription factor onto several locations in the b-globin cluster, in particular, to a region located 5' to the d-globin gene. 5 All these studies allow us to draw a network of co-operating transacting factors (KLF1, SOX6, GATA1 and BCL11A) involved in the switch between fetal and adult hemoglobin (Hb). A recent study 6 using the analysis of large deletions has defined a critical area located 5' to the d-globin gene that appears to exert the main repressor activity of BCL11A.However, if the role of the BCL11A binding region is now well documented, no studies have evaluated the consequence of the deletion of that region in terms of HbF output. We report the precise analysis of the correlation between phenotype and genotype of patients displaying a short deletion (under 25 kb) differing at the 5' d-globin gene breakpoint. The short length of the deletions found in our patients makes these events not comparable with hereditary persistence of fetal Hb (HPFH) deletions whose mechanism is likely to bring the 3'HS (3' hypersensitive site) activator site close to the g-globin genes, and thus enhances HbF expression. Design and MethodsA cohort of 10 patients was selected from our DNA bank of patients referred to our laboratory for the molecular analysis of a bthal phenotype. Prior to sampling, patients received genetic counseling and gave their written, informed consent to the study. The selected patients were heterozygous carriers of a short deletion featuring the 5' breakpoint within the gb-d intergenic region. The phenotypic analysis of patients included red blood cell (RBC) count carried out on an automated cell counter, and Hb study using cation exchange high performance liquid chromatography (HPLC) (VARI-ANT II™; Bio-Rad Laboratories, Hercules, CA, USA). 8 The results are shown in Table 1. Relevant hematologic data were obtained to verify that no patient had received a blood transfusion which could compromise data interpretation. This retrospective study was approved by the Institutional Review Board of the Henri Mondor Hospital, Créteil, France.The molecular analysis of the b-globin cluster was achieved including deletion detection using the quantitative multiplex polymerase chain reaction of short fragment (QMPSF) procedure. 9Precise localization of unknown breakpoints was determined using a custom CGH-array chip with high probe density on the b-and aglobin clusters, 10 and achieved by amplification then sequencing, using primers extrapolated from probes flanking the deletions (Online Supplementary Figures S1-S6).In order to evaluate any correlation as precisely as possible, genotyping of the a-globin c...
We have reported the first Tunisian case of triosephosphate isomerase (TPI) deficiency in a 2-year-old girl. She was the first child of a nonconsanguineous couple. The disease included a neonatal onset of chronic hemolytic anemia, recurrent low-respiratory infections then progressive neurological involvement. The diagnosis was made after her death from the TPI values of her parents who exhibited intermediate enzyme deficiency. Molecular study of TPI genes showed that the father and the mother are heterozygous for Glu105Asp mutation. Pediatricians must be alert to the differential diagnosis in patients having hemolytic anemia and other concomitant manifestations.
The preparation of a prenatal diagnosis in a family of North-African origin in which a child received a bone marrow transplant for β-thalassemia major (β-TM), prompted us to make the molecular diagnosis in the parents and siblings. Molecular and phenotype assays were carried on blood samples from the parents and the proband's sister. The father, a 45-year-old man, was found to be heterozygous for a rare mutation in exon 2 [codon 46 (+A), HBB:c.138_139insA] creating a frameshift, while the mother and sister were found to be carriers of the common codon 39 (C>T) stop mutation (HBB:c.118C>T). Because of the bone marrow transplant, proband genotyping was done from a buccal swab and revealed that he is a compound heterozygote for both the codon 46 and codon 39 mutations. In the parents and sister, hematological parameters were those of a thalassemia minor in agreement with the two β(0) mutations found in the family.
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