THE THALASSEMIA SYNDROMES: MOLECULAR CHARACTERIZATION IN THE SPANISH POPULATION

Abstract

This work compiles the results of our research on α- and β-thalassemias, and includes a literature review of the molecular genetics of α- and β-thalassemias in Spain. We studied 1,564 subjects with thalassemia (294 with β-thalassemia and 1,264 with α-thalassemia) by molecular biology techniques. In relation to β-thalassemia, a total of 15 different mutations were characterized in a study of 308 chromosomes belonging to 294 unrelated subjects. Eleven were homozygotes (22 alleles), three compound heterozygotes (6 alleles), and the remaining 280 were heterozygotes (280 alleles). A total of 86.6% of the alleles identified can be grouped into five different mutations [IVS-I-1 (G → A), IVS-I-6 (T → C), IVS-I-110 (G → A), codon 39 (C → T), codons 8/9 (+G)]. In 14 subjects (4.5%), all heterozygotes, it was not possible to identify the alteration responsible for the β-thalassemia.

For α-thalassemia, 911 subjects showed heterozygous α⁺-thalassemia (872 with −3.7 kb; 14 with −4.2 kb; two with the deletion of 3.5 kb of DNA, and 23 with nondeletional α-thalassemia). Two hundred and thirty-three subjects had homozygous α⁺-thalassemia (223 for –α^−3.7/–α^−3.7); one for –α^−4.2/–α^−4.2; six for –α^−3.7/–α^−4.2; one for –α^−3.5/–α^−3.7; one for αα^Nco/αα^Nco; one for α^Hphα/α^Hphα). One hundred patients presented with heterozygous α⁰-thalassemia (18 of whom were progenitors of patients with Hb H disease). The α⁰ determinant was found in 20 patients with Hb H disease associated with –α^−3.7. From the DNA analysis were identified the ––^MED, ––^SEA, ––^SPAN deletions and the ––^CAL, ––^CANT, and ––^MA mutations; in three cases, a break that affects the distal portion of the short arm of chromosome 16; one of these was associated with the ATR-16 (α-thal with mental retardation) syndrome. Triplication of the α genes (ααα^−3.7/αα) was found in 25 subjects, 16 of whom were associated with a heterozygous β-thalassemia. Only one patient was homozygous for the triplication of α genes (ααα^−3.7/ααα^−3.7) that was associated with a heterozygous β-thalassemia.

In the Mediterranean region preventive programs for thalassemia, based on the detection of heterozygote carriers and genetic advice, are not sufficient to reduce the incidence of newborns with major thalassemia. Prenatal diagnosis of thalassemias has given a new dimension to the prevention of these, but in order to implement this, a knowledge of the mutations and the incidence of these, is essential. This study, therefore, aims to give a general picture of the molecular genetics of thalassemia and its geographical distribution in our area.