Hb S/b + -thalassemia due to Hb sickle and a novel deletion of DNase I hypersensitive sites HS3 and HS4 of the b locus control region Sickle cell disease (SCD) is one of the most common genetic disorders worldwide and is associated with episodes of acute pain and progressive multi-organ damage. 1 The most common cause of SCD is homozygosity for the hemoglobin sickle (Hb S) mutation, with a minority of cases due to compound heterozygosity for Hb S and other alleles including b-thalassemia. Loss-of-function point mutations of the b-globin gene that abolish (b 0 ) or reduce (b + ) production of normal b-chains are the most common causes of b-thalassemia, with large deletions or rearrangements accounting for a small minority of b-thalassemia alleles.2,3 While patients with Hb S/b 0 -thalassemia generally have severe SCD, the residual production of normal b-chains in Hb S/b + -thalassemia patients is associated with lower Hb S concentration in erythrocytes and a less severe disease. 4 Here, we report the unusual case of an infant who had a newborn screening profile fully consistent with sickle trait, yet was diagnosed later in childhood with typical Hb S/b + -thalassemia. Molecular testing demonstrated that the child was a compound heterozygote for the Hb S mutation and a partial deletion of the b-globin Locus Control Region (bLCR). The deletion removed two of the five DNase I hypersensitivity (HS) regions, providing valuable insight into the roles of individual HS regions in globin gene switching and expression. The proband is now a 6-year old boy who was born to healthy non-consanguineous parents of Caribbean descent. The pregnancy and delivery were unremarkable with no evidence of perinatal anemia or jaundice. Newborn screening was negative for SCD, with the Hb profile being fully consistent with sickle trait (Hb F 79.1%, Hb A 6.0%, Hb S 4.0%, Hb Bart's 9.1%) ( Figure 1A). The patient enjoyed normal health until five years of age, when he was diagnosed with SCD during an admission for unexplained abdominal pain and enlarged spleen (splenic sequestration). Microcytosis, sickle erythrocytes, Howell-Jolly bodies and target cells were observed on the peripheral blood smear. Hemoglobin analysis using high performance liquid chromatography (HPLC) was suggestive of Hb S/b + -thalassemia (Hb A 19.4%, Hb S 72.7%, and Hb A2 2.6%) ( Figure 1B). Since diagnosis, the patient has been admitted for one vasoocclusive event and had a tonsillectomy for obstructive sleep apnea. Nucleotide sequence analysis of the β-gobin gene revealed that the proband was heterozygous for the Hb S mutation (HBB:c.20A>T) with no other mutations of the b-globin gene. Deletion-specific gap-PCR demonstrated that he was also heterozygous for the rightward 3.7 kb single a-globin gene deletion (−a 3.7 /aa). Sequence analysis of the intact aglobin genes failed to detect any point mutations. As this genotype could not explain the reduced expression of Hb A and the SCD phenotype in the proband, we investigated the possibility of compound heterozygosity f...
We report four unrelated families with a mild β(+)-thalassemia (β(+)-thal) allele consisting of two sequence variants at the 3' end of IVS-II: IVS-II-839 (T>C) (HBB: c.316-12T>C) and IVS-II-844 (C>A) (HBB: c.316-7C>A). These sequence variants alter the conserved polypyrimidine tract of the consensus splice acceptor sequence (Y11NYAG/G), which could reduce splicing efficiency. This may represent a common, yet under-diagnosed β(+)-thal allele in African populations.
We report the case of a father and daughter who are heterozygous for a duplication of 65 bp within exon 2 of the β-globin gene, resulting in an altered and truncated β-globin chain that is predicted to be non functional. The β-globin gene mutation is in cis with the common Hb A2 ' missense mutation of the δ-globin gene (HBD: c.49G>C), resulting in β-thalassemia (β-thal) trait with normal levels of Hb A2. This is the second report of this β(0)-thal mutation, and both families were associated with the Hb A2 ' variant and normal levels of Hb A2. Laboratories should be aware of the rare occurrence of β-thal trait with normal levels of Hb A2.
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