The Inheritance of Sickle Cell Anemia

Abstract

IF A DROP OF BLOOD is collected from each member of a randomly assembled series of American Negroes and sealed under a cover slip with vaseline, to be observed at intervals up to 72 hours, in the case of about 8 percent of the individuals composing the series a high proportion of the erythrocytes will be observed to assume various bizarre oat, or holly leaf shapes. This ability of the erythrocytes to sickle, as the phenomenon is commonly described, appears to be attended by no pathological consequences in the majority of these individuals, and they are spoken of as having sicklemia, or the sickle cell trait. However, a certain proportion of the individuals who sickle are the vic4ims of a severe, chronic, hemolytic type of anemia known as sickle cell anemia. This proportion has been variously estimated at between 1: 1.4 (8) and 1: 40 (4). The essential difference between sicklemia and sickle cell anemia appears at present to depend at least in part upon the relative ease with which sickling takes place. In sickle cell anemia the erythrocytes may frequently sickle under the conditions encountered in the circulating blood, whereas in sicklemia sickling does not usually occur under these conditions (12). This difference has been attributed to a greater tendency of the erythrocytes of sickle cell anemia to sickle when the 02-tension is reduced, although recently this viewpoint has been challenged (13). Perhaps because of this differencealthough there may be other factors involved, such as the anisoand poikilocytosis to be observed in some individuals with the disease, and a greater resistance to hemolysis of trait cells when sickled than sickle cell anemia cells when sickled-the erythrocytes of a patient with sickle cell anemia have a greatly shortened life span, both in the individuals with the disease and in normal persons who have been transfused with the cells of sickle cell anemia patients, whereas sicklemia erythrocytes have an normal life span (3, 14). The ability of the red cells to sickle was observed to have a genetic basis not long after sickle cell anemia 1 This investigation was supported in part by a grant from the U. S. Public Health Service. The study has been possible only through the generous cooperation of the Anemia Clinic of the Children's Hospital of Michigan, Detroit, Michigan, The University Hospital of the University of Michigan, Ann Arbor, Michigan, and the Wayne County General Hospital and Infirmary, Eloise, Michigan; all three institutions have made their case records of sickle cell anemia freely available. It is a pleasure to acknowledge my indebtedness to Mrs. Marion Weyrauch for technical assistance, and to Mrs. Laura Williams for case work. was recognized as a clinical entity (5). On the basis of a study of one large family, Taliaferro and Huck (15) postulated that the ability to sickle was due to a single dominant gene. At that time the clinical distinction between sicklemia and sickle cell anemia had not been clearly drawn, and the inference was that this gene was more strongly expressed in some individuals (sickle cell anemia) than in others (sicklemia). This has remained the accepted hypothesis up to the present time. Several years ago the author, in a review on the clinical detection of the genetic carriers of inherited disease (9), was led to suggest an alternative hypothesis-namely, that there existed in Negro populations a gene which in heterozygous condition results in sicklemlia, and in homozygous condition in sickle cell anemia. This hypothesis has a counterpart in the relationship which has been demonstrated to exist between thalassemia major and minor (10, 16). Recently the opportunity has arisen to give this hypothesis a thorough test. There exist a number of arguments permitting a critical decision between the two hypotheses. The present preliminary note will consider only one of these arguments. If the homozygous-heterozygotus hypothesis is correct, then both the parents of any patient with sickle cell anemia should always sickle (barring the occasional role of mutation; see below). If, on the other hand, the disease is due to a dominant gene with variable expression, only one parent need although occasionally, due to the chance marriage of two sicklers, both parents may sickle. In calculating the exact proportion of sicklemia to be expected among the parents of individuals with sickle cell anemia according to the dominant hypothesis, certain assumptions must be made. To the best of the author's knowledge, the question of the phenotype of the homozygote has never been raised by those who have accepted the variable dominant hypothesis of sickle cell anemia. For purposes of calculation we shall assume that under the variable dominant hypothesis all homozygotes have sickle cell anemiaalternative assumptions, such as intra-uterine lethality, are possible. We shall further assume that one in fifty heterozygotes also develops sickle cell anemia. Finally, we shall assume