Leonor Osório-Almeida

Novel promoter and splice junction defects add to the genetic, clinical or geographic heterogeneity of β-thalassaemia in the Portuguese population

SummaryIn order to delineate the spectrum and the relative abundance of β-globin gene defects causing thalassaemia in the Portuguese population, a representative sample was analysed including 51 β-thalassaemia carriers along with 26 patients representing different clinical phenotypes. Seven mutations were identified, four of which [codon 39 (C→T), 39%; intervening sequence (IVS)1 nucleotide (nt) 1 (G→A), 26%; IVS1 nt 110 (G→A), 17%; IVS1 nt6 (T→C), 15%] account for 97% of 93 β-thalassaemia chromosomes. Two previously undescribed mutations, namely a C→T substitution at position — 90 in the proximal CACCC box, and the deletion of nucleotides 4 and 5 (AG) in IVS 2 were identified. The uncommon, though ubiquitous, G→T transversion at codon 121 was found once upon haplotype V. Direct prenatal diagnosis can be offered to 95% of couples at risk of bearing a thalassaemic child.

The β‐Thalassemia Mutation/Haplotype Distribution in the Moroccan Population

The present study compiles the results of our own research and of a prior study on β‐thalassemia (thal) in Morocco, comprising a total of 187 β‐thalassemic chromosomes. Six major mutations: (β0) codon 39 (C→T), (β+) IVS‐I‐6 (T→C), (β0) frameshift codon (FSC) 6 (− A), (β0) FSC 8 (− AA), (β0) IVS‐I‐1 (G→A) and (β+) − 29 (A→G) account for 75.7% of the independent chromosomes studied. A regional predominance was observed (Gharb and West regions) for the (β+) IVS‐I‐6 (T→C) mutation. Despite an observed heterogeneity of molecular anomalies, a direct method of diagnosis of the prevalent mutations is feasible in this population. The distributions of mutations and haplotypes are in conformity with the geographical location of Morocco and the historical links with both the Mediterranean communities that have successively interspersed with the Berbers, the Phoenicians, the Carthaginians, the Romans, the Arabs, the population of the Iberian Peninsula and, to a lesser degree, the Vandals and the Byzantines and permanently, with the Sub‐Saharan Africans. In the adult population, the levels of fetal hemoglobin (Hb) in heterozygotes vary from trace quantities to 2.38 g/dL of total Hb. With the exception of the (β0) codon 39 (C→T) nonsense mutation, no statistically significant correlation was found, neither between mutation and Hb F levels, nor gender and Hb F levels in heterozygotes. The genetic markers for Hb F increase, located within cis active sites such as the XmnI site at − 158 bp of the Gγ‐globin gene and the ATXTY repeat region at − 540 bp of the β‐globin gene, were assessed. The polymorphism XmnI shows linkage disequilibrium with haplotypes III, IV and IX, as previously observed in the Algerian, Sicilian and Portuguese β‐thal populations. Contrary to what has previously been reported for a population of β‐thal carriers of European descent, this sample does not show a statistically significant correlation between Hb F levels and the presence of the genetic markers XmnI restriction site at − 158 bp of the Gγ‐globin gene and ATXTY alleles at 5′ of the β‐globin gene.

A novel mosaic Bantu/Benin/Bantu βs haplotype found in several African populations

In a survey of the chromosomal backgrounds associated with the sickle cell gene in Portuguese-speaking populations from Europe and Africa, a discordance between the classical haplotype and the predicted allele at theRsaI polymorphism 5′ to the β globin gene was observed in four patients. Extensive typing of the corresponding βs chromosomes at simple polymorphic repeat motifs revealed a novel “extended” haplotype that appeared to be a mosaic of (1) a Bantu-type DNase I hypersensitive site 2 within the β globin gene cluster locus control region, (2) a Benin 5′ subhaplotype, and (3) a Bantu 3′ subhaplotype. We propose two alternative schedules for the generation of yet another chromosomal background of the sickle cell gene.

A novel rearrangement of the human fetal globin genes leading to a six γ-globin gene haplotype

Summary. Haematological as well as gene mapping data are reported for three members of a Portuguese Caucasian family with high Gγ‐globin levels. A gamma‐globin gene sextuplication of the GγAGγAGγAGγAGγAγ type was present in the proband and her father. Comparison of gene mapping data with quantitative results of fetal haemoglobin (HbF) analysis provided an explanation for the extremely high Gγ‐globin levels (> 90%) in the HbF from the two mentioned individuals. This rearrangement, for which a generation mechanism is proposed, is the first gamma‐globin gene sextuplication described in the literature.