Sickle cell disease caused by heterozygosity for Hb S and novel LCR deletion: Report of two patients

Abstract

The β-globin gene LCR is located ∼6 kb upstream of the embryonic ε-globin gene, and is made up of five DNase I hypersensitive sites (HSs), HS 1-5. LCR plays a pivotal role in regulating the expression of downstream ε-, Gγ-, Aγ-, δ-, and β-globin genes in cis [1]. Deletions removing the LCR and parts of the downstream β-globin gene cluster in patients have been described [2]. These individuals present with a (γδβ)0-thalassemia carrier phenotype. We now report two patients with severe sickle cell disease who were compound heterozygous for Hb S mutation and novel LCR deletion. In one case, HS 1-3 were deleted; in the other, HS 1-5 were deleted. In both cases, the β-like globin genes in cis to the LCR deletions were intact. Genotypically, both patients appeared to have sickle cell trait. Coinherited with either LCR deletion, these individuals presented as sickle cell disease patients. The breakpoints of these LCR deletions were defined. These results affirm that HS 2 and 3 are primarily responsible for conferring erythroid specific high-level expression of cis-linked β-like globin genes. Furthermore, LCR deletions might cause hemolytic disease of newborns.