Prenatal diagnosis of thalassemias and hemoglobinopathies

Abstract

Thalassemia syndromes and hemoglobinopathies are of clinical genetic significance because of the severity of the sequelae associated with particular genetic constitutions in these conditions, their occurrence at high frequencies in certain populations of Mediterranean, African, and Asian origin, and the high frequency of recurrence in pregnancies of at risk families. Application of recently developed techniques of molecular genetics to the antenatal diagnosis of the most deleterious of these conditions (homozygous β-thalassemia [Cooley/s anemia], homozygous α-thalassemia [Barts Hydrops fetalis], sickle cell anemia, and related severe homoglobinopathies) now affords parents the option to interrupt a pregnancy in which the fetus has the genetic constitution causing one of these abnormalities. The 2 different analytical strategies utilize fetal cells obtained by aminocentesis. In 1, fetal blood is obtained either by sonographically guided placental aspiration or by aspiration from a placental vein directed by fetoscopy. Globin chain synthesis is monitored by the incorporation of radiolabelled amino acids in the isolated erythrocytes and the determination of the ratio of radioactive label incorporated into the various globin chains separated by column chromatography or electrophoresis. This technique is applicable to the antenatal diagnosis of α- and β-thalassemia and to selected hemoglobinopathies. However, in the most experienced centers, fetal blood sampling is associated with a greatly increased risk of fetal loss. The other analytical approach utilizes desoxyribonucleic acid (DNA) isolated from fibroblasts to evaluate the presence of quantitatively and/or qualitatively normal DNA sequences, which constitute the structural gene(s) encoding specific globin polypeptide chains. This approach is most generally applicable to the detection of structural gene deletions as in α-thalassemia; maternal and fetal risk is the same as that for conventional amniocentesis.