Lynda Walker

Three New α-Thalassemia Point Mutations Ascertained Through Newborn Screening

We report three new α-thalassemia (thal) point mutations detected during newborn screening for hemoglobinopathies. The first mutation is a single nucleotide deletion (−A) that abolishes the translation initiation codon of the α2-globin gene, detected in a newborn of Hmong ethnicity who carried the Southeast Asian α0-thal deletion (αTα/– –SEA). The second mutation, a frameshift caused by a single nucleotide deletion in exon 2 of the α1-globin gene [codon 78 (−C)], was detected in a Black/Chinese newborn who also carried the Southeast Asian α0-thal deletion (ααT/– –SEA). The third mutation was a frameshift in exon 3 of the α2-globin gene, codons 113/114 (−C). This mutation was detected in a newborn who carried the 3.7 kb α+-thal deletion (αTα/–α3.7).

Characterization of a rare single alpha-globin gene deletion in a Chinese woman with Hb H disease.

A Chinese patient with Hb H (β4) disease was found to be a compound heterozygote for a 2.4 kb α+-thalassemia (thal) deletion and the common Southeast Asian α0-thal deletion. The endpoints of the 2.4 kb deletion were identified by sequence analysis of the deletion junction. The deletion removes the entire α1-globin gene and leaves the α2-globin gene intact.

Characterisation of a novel 49·3 kb Gγ(Aγδβ)0-thalassaemia deletion in seven families of Asian descent

The human b-globin gene cluster consists of five functional genes located on the short arm of chromosome 11 and arranged in the linear order e-c-c)d)b (centomere fi telomere). More than 40 different deletions of the b-globin gene cluster have been reported, the phenotype of which depends on the number of genes affected (Giardine et al, 2007). The c(cdb)-thalassaemias are due to deletions or rearrangements that abolish expression from the c, d, and b-globin genes while leaving the c-globin gene intact. Ten different c(cdb)-thalassaemia deletions and rearrangements have been reported in a wide range of ethnic groups (Higgs et al, 2001; Wood, 2001). The 5¢ deletion endpoints are tightly clustered immediately upstream and within the c-globin gene, and extend downstream of the b-globin gene for varying distances. Carriers of c(cdb)-thalassaemia typically have mild microcytosis and hypochromia, coupled with elevated levels of Hb F (a2c2). Herein, we describe a novel deletion identified in multiple unrelated individuals with c(cdb)-thalassaemia trait. Southern hybridisation using a probe specific for c-globin genes (c-IVS2) detected the following deletion-specific fragments: Bam HI (4Æ6 kb), Bgl II (8Æ2 kb), Xba I (5Æ9 kb) and Eco RV (9Æ3 kb). Based on the Southern hybridisation results, the 5¢ deletion endpoint was localised to a region immediately

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.

High Hb A2 β-Thalassemia Due to a 468 bp Deletion in a Patient with Hb S/β-Thalassemia

We describe a case of Hb S/β-thalassemia (thal) involving a 468 bp deletion that removes the β-globin gene promoter but leaves the coding regions intact. This is the second report of this deletion, and our family study establishes that this deletion causes β0-thal with unusually high levels of Hb A2 and Hb F. As with other genotypes involving deletions of the 5′ region of the β-globin gene, our patient had a mild form of Hb S/β-thal.

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 three novel delta chain hemoglobin variants and two delta-thalassemia alleles.

We report the characterization of five novel δ-globin gene mutations detected during routine screening for thalassemia. Three missense mutations were identified, resulting in the following δ chain hemoglobin (Hb) variants: Hb A2-Acacias [δ4 (ACT>AGT), Thr→Ser, HBD c.14C>G], Hb A2-Toronto [δ74 (GGC>GAC), Gly→Asp, HBD c.224G>A], and Hb A2-Calgary [δ99 (GAT>GGT), Asp→Gly, HBD c.299A>G]. Two other mutations most likely result in δ0-thalassemia (δ0-thal). One mutation altered the translation initiation codon from ATG to ATA (HBD c.3G>A), and another changed the canonical splice donor sequence of IVS-II from GT to AT (HBD C.315+1G>A).

High Oxygen Affinity Hemoglobin Variant in a Canadian Family: Hb Bunbury [β94(FG1)Asp→Asn, GAC→AAC]

We investigated a three-generation Canadian family in which individuals displayed varying degrees of erythrocytosis due to a high oxygen affinity β chain hemoglobin (Hb) variant [Hb Bunbury, β94(FG1)Asp→Asn, GAC→AAC]. This is the fourth reported case of Hb Bunbury.

α+-Thalassemia Trait Caused by a Nonsense Mutation in the α2-Globin Gene: Codon 54 (CAG>TAG)

We report a new α-thalassemia (α-thal) point mutation detected in a woman with α+-thal trait. Sequence analysis identified a nonsense mutation in exon 2 of the α2-globin gene, at amino acid codon 54 (CAG>TAG).