Thalassemia intermedia as a result of heterozygosis for ß0-thalassemia and <FONT FACE=Symbol>aaa</FONT>anti-3.7/<FONT FACE=Symbol>aa</FONT> genotype in a Brazilian patient

Abstract

We report a case in which the interaction of heterozygosis for both the ß 0 -IVS-II-1 (G→A) mutation and the ααα anti-3.7 allele was the probable cause for the clinical occurrence of thalassemia intermedia. The propositus, a 6-year-old Caucasian Brazilian boy of Portuguese descent, showed a moderately severe chronic anemia in spite of having the ß-thalassemia trait. Investigation of the α-globin gene status revealed heterozygosis for α-gene triplication (ααα/αα). The patient's father, also presenting mild microcytic and hypochromic anemia, had the same α and ß genotypes as his son, while the mother, not related to the father and hematologically normal, was also a carrier of the ααα anti-3.7 allele. The present case emphasizes the need for considering the possibility of α-gene triplication in ß-thalassemia heterozygotes who display an unexpected severe phenotype. The ß-thalassemia mutation found here is being described for the first time in Brazil.

Frequency of α-Globin Gene Triplications and Their Interaction with β-Thalassemia Mutations

“…However, the average hematological phenotypes, observed for the single b-thal traits and for the same traits in combination with a-triplications in this study, indicate only a marginal difference with possibly some increased red cell turnover or hemolysis. The general idea that an extra a gene could aggravate the mild phenotype of the b-thal carrier to the level of an intermediate (19)(20)(21)(22) is not sustained by the data observed in the present cohorts (Table 2). Our recent studies (23) report a significant phenotype aggravation in b-thal carriers in the presence of two extra a genes (aaaa/aa) and transfusion dependency starting with three extra active a genes (aaaa/aaa).…”

The molecular basis of beta-thalassemia intermedia in southern China: genotypic heterogeneity and phenotypic diversity

“…The 11 known β-thalassemia mutations including -29(A→G), -28 (A→G), CD17 (A→T), β E (CD26 G→A), IVS-1-1(G→T), IVS-1-5(G→C), CD27-28(+T), CD41-42 (-CTTT), CD43 (G→T), CD71-72(+A) and IVS-2- 654(C→T) [1], the two common deletions including Chinese G γ + ( A γδβ 0 ) thalassemia [22] and Southeast Asian hereditary persistence of fetal hemoglobin (SEA-HPFH) [23], the three common α-thalassemia deletions (-- SEA , -α 3.7 and -α 4.2 ) [1], the six non-deletional mutations (α cd30 ,α cd31 ,α cd59 ,α QS ,α CS , and α WS ) [1], the ααα anti-3.7 or ααα anti-4.2 triplication [24,25] and XmnI site -158 of the G γ-globin gene [26,27] were analyzed by previously described methods. Further sequence analysis was applied on both β 0 /β 0 and β + /β N or β 0 /β N samples, analyzed targets for the former (β 0 /β 0 ) include both 3'HS1 and 5'HS2 core region, the promoters of the G γ- and A γ-globin genes, the (AT)x(T)y sequence variations at the position -540 of the β-globin gene, a single-nucleotide polymorphism (SNP) of rs11886868 in the BCL11A gene, as well as the whole α2- and α1-globin genes; and those for the latter (β + /β N or β 0 /β N ) include the core regions of both 5'HS2 and 5'HS3, the whole β-globin gene and AHSP gene, and the full-lenghth cDNA of GATA-1 generated by RT-PCR from mRNA.…”

Copy number variations of six and seven α-globin genes in a family with intermedia and major thalassemia phenotypes

“…We do believe that this is the first report of a-globin locus rearrangements, other than the most common rearrangement (aaa anti 3.7 triplication), in combination with simple heterozygosity for the common b + -thal mutation seen in the Iranian population, to the best of our knowledge. These multiplications of a-globin genes may explain, at least, a part of the many unclear cases of severe phenotype in b-thal carriers [22,23]. Moreover, it is a general idea that one extra a-globin genes could aggravate the mild phenotype of the b-thal carrier to the level of an intermediate phenotype at least in Iranian population [4].…”