Mild β⁺-Thalassemia Associated With Two Linked Sequence Variants: IVS-II-839 (T>C) and IVS-II-844 (C>A)

Abstract

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.

Very mild forms of Hb S/beta+-thalassemia in Brazilian children

“…According to our findings and those of other investigators, 3,4 both the −92 (C>T) mutation and the IVS-II-844 (C>A)/IVS-II-839 (T>C) combination cause a very mild form of Hb S/β + -Thal. These mutations do not fit into the Hb S/β + -Thal phenotypic classification as proposed by Serjeant et al based on the amount of Hb A produced.…”

“…It modifies the conserved polypyrimidine tract of the splice acceptor site causing a reduction of beta globin chain expression to around 60% of normal. 4,6 Carriers of the mutations described in this report showed a mean Hb A level of 39.7% and were oligosymptomatic. This finding is consistent with the first report of these two variants in four unrelated Canadian families of African ancestry.…”

“…The probands were asymptomatic Hb S/β + -Thal patients and the adults had Hb A levels of about 44%. 4 This is the second study worldwide to report these two linked sequence variants in cis . The IVS-II-844 mutation has also been identified in beta-thalassemia patients without the concomitant IVS-II-839 mutation being reported.…”

“… 3 Recently, a combination of two sequence variants, IVS-II-839 (T>C) and IVS-II-844 (C>A), was associated with a very mild phenotype of sickle cell disease (SCD). 4 Because of the marked clinical variability of Hb S/β + -Thal patients, molecular predictors of disease severity would be helpful to guide treatment choices in children with this genotype. The objective of this study was to characterize the hematological parameters, clinical features, and molecular basis of very mild forms of Hb S/β + -Thal in a newborn cohort of Minas Gerais state, Brazil.…”

Single‐nucleotide substitution T to A in the polypyrimidine stretch at the splice acceptor site of intron 9 causes exon 10 skipping in the ACAT1 gene

“…It has been reported that ag dinucleotides in polypyrimidine stretches are very rare. There are also few reports describing that single-nucleotide substitutions in polypyrimidine stretches of splice acceptor sites were proved to cause aberrant splicing (Montejo et al 1999;Ogawa et al 2000;Carboni et al 2011;Ben Rhouma et al 2013;Lewandowska 2013;Waye et al 2013;Mattioli et al 2014). We thus examined whether in silico tools can predict splice aberration caused by these polypyrimidine stretch mutations (Table 1).…”