Loss of Major DNase I Hypersensitive Sites in Duplicated β-globin Gene Cluster Incompletely Silences HBB Gene Expression

We report an infant with sickle cell disease phenotype by biochemical analysis whose β-globin gene (HBB) sequencing showed sickle cell mutation (HBB^S) heterozygosity. The proband has a unique head-to-tail duplication of the β-globin gene cluster having wild-type (HBB^A) and HBB^S alleles inherited from her father; constituting her HBB^S/HBB^S-HBB^A genotype. Further analyses revealed that proband's duplicated β-globin gene cluster (∼650 kb) encompassing HBB^A does not include the immediate upstream locus control region (LCR) or 3′ DNase I hypersensitivity (HS) element. The LCR interacts with β-globin gene cluster involving long range DNA interactions mediated by various transcription factors to drive the regulation of globin genes expression. However, a low level of HBB^A transcript was clearly detected by digital PCR. In this patient, the observed transcription from the duplicated, distally displaced HBB^A cluster demonstrates that the loss of LCR and flanking 3′HS sites do not lead to complete silencing of HBB transcription.