Lisa M. Nakamura

Three New β-Globin Gene Promoter Mutations Identified Through Newborn Screening

We report three new β-globin gene promoter mutations identified in newborns with hemoglobin (Hb) profiles consistent with Hb S/β+-thalassemia (thal) (Hbs FSA). All three mutations are in close proximity to the conserved ATAA sequence located at positions −31 to −28 relative to the mRNA Cap site. Two cases involved single base substitutions at positions −25 (G→C) and −32 (C→T). The remaining case involved the deletion of two bases (−AA) at positions −27 and −26.

Hb S/β+-thalassemia due to Hb sickle and a novel deletion of DNase I hypersensitive sites HS3 and HS4 of the β 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][1] The most common cause of SCD is homozygosity for the hemoglobin sickle (Hb S) mutation, with a minority of cases due to compound

Normal Hb A2 β-Thalassemia Trait: Frameshift Mutation (HBB: c.187_251dup) in Cis with the Hb A2’ δ-Globin Gene Missense Mutation (HBD: c.49G>C)

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 β0-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.

Characterization of Two Novel Deletions Involving the 5′ Region of the β-Globin Gene

Abstract We report two novel β-thalassemia (β-thal) deletions involving the 5′ region of the β-globin gene (HBB). The first deletion spans 538 bp and removes the β-globin promoter, 5′ untranslated region (5′UTR) and most of exon 1. This deletion was identified in a 3-year-old Vietnamese boy with non transfusion dependent Hb E (HBB: c.79G>A)/β0-thal. The second deletion spans 1517 bp and removes the β-globin gene promoter, 5′UTR, and exons 1 and 2. This deletion was identified in two unrelated adults of European descent who had β-thal trait with unusually high Hb A2 levels. Deletions such as these are generally associated with higher levels of Hb A2 and Hb F than typical β-thal alleles, which may ameliorate the severity of the disease.

α0-Thalassemia Due to a 90.7 kb Deletion (– –NFLD)

Abstract We report an α0-thalassemia (α0-thal) trait in Newfoundlanders caused by a novel 90.7 kb deletion. The deletion, designated the Newfoundland deletion (– –NFLD), removes both the HBA2 and HBA1 genes, while leaving the HBZ gene intact. The 5′ deletion endpoint is within the HBAP1 pseudogene, approximately 3.7 kb upstream of the HBA2 gene. The 3′ deletion endpoint is approximately 82.5 kb downstream of the HBA1 gene, within the second intervening sequence (IVS-II) of the FAM234A gene. This is the second α0-thal deletion reported in Newfoundland families of northern European descent.

Novel Mutation of the Translation Initiation Codon of the α1-Globin Gene (ATG>AAG or HBA1:c.2T>A)

Abstract We report two Italian–Canadian families with α+-thalassemia (α+-thal) trait caused by a novel mutation of the translation initiation codon of the α1-globin gene (ATG>AAG or HBA1:c.2T>A). This is the tenth reported α-thal mutation involving the translation initiation codon or the conserved Kozak consensus sequences of the HBA2 or HBA1 genes.

α+-Thalassemia Due to a Frameshift Mutation of the α2-Globin Gene [codons 55/56 (+T) or HBA2: c.168dup]

Abstract We report a case of α+-thalassemia (α+-thal) trait in a Chinese-Canadian family caused by a novel frameshift mutation of the α2-globin gene, specifically the duplication of a single nucleotide at amino acid codon 56 [HBA2: c.168dup]. The mutation results in substitution of a termination codon (TAA) for lysine (AAG) at amino acid position 56.

Hb North York [β117(G19)His→Asp]: A New β Chain Hemoglobin Variant

Routine hemoglobin (Hb) analysis identified a new β chain Hb variant in an Iranian woman, who otherwise had normal hematological indices. Sequence analysis demonstrated that the Hb variant was due to a missense mutation at amino acid codon 117 (CAC>GAC, His→Asp) of the β-globin gene.