Two novel mutations in the 3′ untranslated region of the beta‐globin gene that are associated with the mild phenotype of beta thalassemia

Abstract

Based on the observed β-thal intermedia phenotypes and the accompanying mutations, we conclude that these novel β-globin gene 3' UTR mutations are associated with the mild phenotype of β-thal.

NAA10 polyadenylation signal variants cause syndromic microphthalmia

“…The contribution to milder phenotypes has two implications; first, in disorders where loss of gene function would be lethal, PAS variants may allow sufficient function for viability. Second, for disorders where the phenotype is due to complete loss of function, PAS variants may be missed if they lead to a milder condition 36. We conclude from these data that the phenotypic consequence of pathogenic PAS variants is likely due to loss or partial loss of function, consistent with the experimental observations of these variants in other genes and the qPCR data we show here.…”

“…The NAA10 3′ UTR variant identified in family 1, c.*43A>G, alters the AATAAA consensus to AATAGA, similar to the c.*112A>G (reference cDNA NM_000518.4) pathogenic variant in the beta globin ( HBB) gene (Human Gene Mutation Database [HGMD] CR900266) (see table 1). 35 The 3′ UTR variant of NAA10 identified in family 2, c.*39A>G, alters the AATAAA consensus to GATAAA, similar to another reported pathogenic variant in the HBB gene (c.*108A>G, HGMD CR127145) 36. The NAA10 3′ UTR variant identified in family 3, c.*40A>G, alters the AATAAA consensus to AGTAAA, similar to the variant in the ARSA gene (HGMD CR890137) reported by Gieselmann et al 37 and a variant in the SLC6A4 gene (HGMD CR102248) reported by Gyawali et al ,38 although it is important to note that the wild-type PAS consensus sequence in both ARSA and SLC6A4 genes is AATAAC (see table 1).…”

“…HBB and HBA2 lie in the middle of the range at about 1% of variants, reflecting the large number of variants in these well-studied genes. Most of the clinical phenotypes associated with PAS variants are typical of those seen for loss of function variants in the same gene, although they may be found with milder forms of the phenotypes; for example, in HBB ,36 43 the phenotypes of PAS variants are described as either typical or mild thalassaemia. The contribution to milder phenotypes has two implications; first, in disorders where loss of gene function would be lethal, PAS variants may allow sufficient function for viability.…”

Premarital Genetic Diagnosis Revealed Co-heredity Nature of Beta Globin Gene 25-26 del AA and 3’UTR+101 G-C Variants in Two Beta Thalassemia Heterozygotes

“…3’UTR+101 G-C being a single nucleotide variant resulting in a decreased expression of the gene causing the beta thalassemia major clinical picture is the most likely one. This is more evident when combined with a disease causing mutation, as previously reported by us and others [3,4,5,6,7]. However, from our family’s data, this is not valid, because they are beta thalassemia carriers.…”

Novel Βeta (β)-Thalassemia Mutation in Turkish Children

“…b-Thal, is the most frequently observed hereditary blood disorder in the world, is characterized by deficiency of hemoglobin b-globin gene and also is a profoundly heterogeneous, both at the molecular and clinical level [1,10]. Approximately 300 different b-globin gene mutations for b-Thal have been reported and 40 of them are common in Turkey [11].…”