Heterogeneity of the ɛγδβ‐thalassaemias: characterization of three novel English deletions

Abstract

Heterogeneity of the ecdb-thalassaemias: characterization of three novel English deletionsThe thalassaemias are inherited disorders classified genetically into a,b,c,db,d and ecdb varieties according to the type of globin(s) that are under-produced (Weatherall & Clegg, 2001). ecdb-thalassaemias are all caused by deletions of the b-globin gene cluster on chromosome 11p. At the molecular level, the deletions fall into two categories: group I removes all, or a greater part of the b-globin cluster, including the b-globin gene. Group II removes extensive upstream regions leaving the b-globin gene itself intact despite which, its expression is silenced because of inactivation of the upstream b-locus control region (b-LCR) (Grosveld et al, 1993). However, because of incomplete sequence data, the breakpoints of many of the early deletions have not been characterized. Recently, two novel deletions causing ecdb-thalassaemia have been reported; a 153 kb deletion removing the entire b-globin cluster (group I) in a Chilean family (Game et al, 2003), and an upstream deletion of 112 kb (group II) in a Dutch family (Dutch III) (Harteveld et al, 2003). The present study describes the characterization of three novel ecdb-thalassaemia deletions, in three English families, named English II, III and IV, to differentiate them from the previously reported English (I) deletion (Curtin et al, 1985).English II removes 98 kb extending from 8 kb upstream of the G c-globin gene, thus leaving the G c, A c and b-genes intact.English III and IV remove the entire b-globin cluster including several flanking olfactory receptor (HOR) genes. English IV removes more than 400 kb of this region of chromosome 11p and is the largest deletion reported so far. Although in later life, heterozygotes for ecdb-thalassaemia have a blood picture typical of b-thalassaemia trait but with normal A 2 levels, our

The Problem of Borderline Hemoglobin A2 Levels in the Screening for β-Thalassemia Carriers in Sardinia

“…Subjects with borderline HbA2 levels in association with abnormal red cell indices should be carefully investigated because their phenotype may be the result of the coinheritance of β- and δ-thalassemia alleles in cis or in trans, mild β-thalassemia mutations or the presence of unusual cluster deletions, such as εγδβ-thalassemias or LCR deletions [1,12,13,14,15]. The identification, the molecular procedure and the exact diagnosis of individuals with borderline HbA2 levels in the absence of hematological changes is difficult, especially if the in vitro globin chain synthesis analysis to exclude α/β chain imbalance is not available.…”

Severe intrauterine anemia: a new form of thalassemia presenting in utero in a Norwegian family

“…Many (14/18) of the previously published families 3 have been described in Northern Europeans but this almost certainly reflects ascertainment bias, with such cases standing out in populations where the common forms of thalassemia are not prevalent.…”

“…8 The Norwegian deletion, like almost half of the previously described εγγδβ thalassemia cases, spares the β globin gene itself but the loss of the LCR leaves the gene inactive. The molecular deletion in each has been unique to the family in which it was found 1,3 and the Norwegian case is no exception. This makes it likely that the condition is maintained by recurrent mutation and hence is a potential diagnosis even in populations not normally associated with thalassemia.…”

Anemia in the Neonate: The Differential Diagnosis and Treatment

“…Deletion of a single complete beta-globin gene locus, although exceptionally rare, can lead to significant hemolysis during the neonatal period without abnormalities on hemoglobin electrophoresis. 2,3 Another hemoglobinopathy associated with critically ill infants and hemolytic anemia is alpha thalassemia with deletion of all four alpha globin genes, also called hydrops fetalis. These fetuses are often lost due to spontaneous miscarriages in-utero.…”