Three Mexican Families with β thalassemia intermedia with different molecular basis

Abstract

Beta thalassemia (β-thal) is a frequent monogenic disease, is clinically and molecularly heterogeneous. This study described molecular and laboratory findings for three Mexican patients with β-thal intermedia phenotype and their relatives. Three Mexican families were studied for presenting β-thal intermedia, ARMS-PCR and Gap-PCR were performed to screen for common mutations, Sanger sequencing for rare or new alleles, and MLPA for identifying deletions and or duplications. In all three families we observed, in heterozygote condition, the mutation c.118C > T (p.Gln39*) also known as codon 39(C > T) in the β globin gene (HBB) associated with a novel molecular defect: a new duplication of the alpha globin gene cluster, a new deletion that includes the loss of exon 3 of HBB and finally a novel mutation in the 3'UTR of HBB (HBB: c.*132C > A). We report three Mexican families with beta thalassemia intermedia due to different molecular basis; a new single nucleotide mutation involving the last nucleotide of the β-globin chain transcript; and two possible new DNA rearrangements, an α cluster duplication, and a partial β gene deletion.

Figure 1. Schematic representation of three globin gene mutations associated with HBB.c:118C > T in patients with β-thal intermedia. A) α-cluster duplication from Family 1. Duplication is shown in dark grey shade, uncertain breakpoints are indicated in light grey shade; MCS-R sequences are numbered from 1-4; involved MLPA probes are specified by (a) 463 bp 19236-L25316, (b) 283 bp 04638-L23602, and (c) 310 bp 04639-L04020. B) HBB 3’ deletion from Family 2. Deletion is indicated in dark grey shade, uncertain breakpoints are shown in light grey shade involved MLPA probes are presented by (a) 196 bp 05833-L05335, (b), 166 bp 11884-L12684 (c) 206 bp 11885-L13080, (d) 173 bp 05836-L06321; (e) 274 bp 11980-L12803. C) HBB:c.*132C > A point mutation found in Family 3. Nucleotide change is indicated with an arrow. Nucleotides in capital letters represent transcribing sequence.