Molecular Genetic Studies in Black Families with Sickle Cell Anemia and Unusually High Levels of Fetal Hemoglobin

Abstract

Clinical, hematologic, and molecular genetic studies are reported for five families with SS patients having unusually high fetal hemoglobin (Hb F) levels (mean 28.3%, range 19-42%). Some of the individuals were symptom-free and one was not anemic. However, some were symptomatic despite a very high Hb F. Neither the Hb F level nor the F cell distribution entirely explained the variation in clinical severity. Molecular genetic studies identified the Senegal haplotype with the associated -158 G gamma (C----T) mutation in two of the five families. The -202 G gamma (C----G) mutation was not found in any of the individuals studied. Sequencing of the gamma-globin gene promoters to detect genetic high F determinants not detectable by restriction digestion was not performed. All AS parents and AS siblings demonstrated elevated F cells when the Senegal/-158 G gamma (C----T) mutation was present with either the beta S or beta A allele. Double heterozygosity for two different high F determinants in some SS patients is suggested by the studies in at least one family. Discordance among siblings in clinical and hematologic manifestations in two families provides additional evidence for loci regulating Hb F cell production which are not linked to the beta-globin gene clusters.

β‐Globin gene cluster haplotypes and HbF levels are not the only modulators of sickle cell disease in Lebanon

“…This finding supports the possibility mentioned above that transacting determinants of high HbF levels unlinked to the β ‐globin gene cluster exist, and provides evidence that high HbF levels alone are not sufficient to ameliorate the severity of clinical symptoms. Our findings support the conclusion by Acquaye et al (24) and Seltzer et al (25), that fetal hemoglobin levels are important but not the only parameters that affect the severity of the disease.…”

Sudden unexpected death in an undiagnosed sickle disease

“…Seltzer et al observed five black families with high HbF levels who had varying degree of severity even in patients with similar HbF levels. [8] Our patient had a preterminal HbF level of 23.1 gms /dl which is consistent with Kar et al findings in Indian patients. [5] Whether this factor contributed to her previous asymptomatic status cannot be commented upon with certainty.…”

Haplotypes, Sub-Haplotypes and Geographical Distribution in Omani Patients with Sickle Cell Disease

“…This finding imply that other circumstantial or genetic factors or external transacting determinants such as blood viscosity, elevated packed cell volume, vascular adherence, acidosis and dehydration as well as patient's life style and diet might contend with the beneficial effect of the high HbF level. Our findings support the conclusion by Acquaye et al 29 and Seltzer et al 30 that fetal hemoglobin levels are very important but not the only parameters that mitigate the severity of the disease and we are at the moment inquiring which other factors could be associated with the severity of this case.…”