Asymptomatic and mild beta-thalassemia in homozygotes and compound heterozygotes for the IVS2+1G-->A mutation: role of the beta-globin gene haplotype.
OBJECTIVE
We report on two families in which the beta(0)-thalassemia mutation IVS2+1G-->A occurs either in the homozygous or compound heterozygous condition with other beta-thalassemia determinants. In the first family the proband, homozygous for the IVS2+1 determinant, is asymptomatic and was detected by chance during a screening program for beta-thalassemia. In the second family, the proband is a 43-year old female with a very mild thalassemia intermedia due to compound heterozygosity for the IVS2+1G>A and IVS1+110G>A mutations. Her father was diagnosed as having a thalassemic disorder only during the family studies carried out because of the proband's condition. He is a compound heterozygote for the Sicilian type deltabeta(0)-thalassemia and the IVS2+1 mutation and has a normal level of hemoglobin.


METHODS
In both families, the heterozygous carriers of the IVS2+1G>A have unusually elevated levels of fetal hemoglobin (HbF), and the homozygotes showed 98% HbF, reflecting an increased production of well hemoglobinized F-cells not associated with a significant erythroid expansion.


RESULTS
The high HbF levels co-segregate with the beta-thalassemia mutation; the size and structure of both pedigrees do not allow the contribution of unlinked genes to the elevated production of HbF to be assessed.


CONCLUSIONS
We propose that the unusual phenotypes resulting from homozygosity and compound heterozygosity for IVS2+1 are, against the background of a polygenic quantitative control of HbF expression, principally due to elements, such as repetitive sequences or single nucleotide polymorphisms, within or closely linked to the beta-gene cluster. These are potentially implicated in chromatin environment modifications, and could, therefore, be responsible for sustained HbF synthesis during development.
Ragusa
Angela
A
Laboratorio di Patologia Genetica, IRCCS Oasi Maria SS, Troina (EN), Italy. citogenetica1@ao-vittorioemauele.it
Amata
Silvestra
S
Lombardo
Turi
T
Castiglia
Lucia
L
Maier-Redelsperger
Micheline
M
Labie
Dominique
D
Bernini
Luigi
L
D000293:Adolescent; D000328:Adult; D005260:Female; D005319:Fetal Hemoglobin / Q000378:metabolism; D005914:Globins / Q000235:genetics*; D006239:Haplotypes / Q000502:physiology*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D017086:beta-Thalassemia / Q000097:blood / Q000473:pathology*
D005914:Globins; D005319:Fetal Hemoglobin