Silent β-Thalassemia Mutations at −101 (C>T) and −71 (C>T) and Their Coinheritance with the Sickle Cell Mutation in Bahrain

Abstract

Silent β-thalassemia (β-thal) is a group of mutations affecting the β-globin gene that cannot be differentiated in heterozygote states from normal conditions by using conventional criteria for the diagnosis of β-thal trait. Here we report the existence of two silent β-thal mutations in the population of Bahrain, one at -101 (C>T) and the other at -71 (C>T). We screened 126 healthy individuals with high-normal Hb A2 levels and found a frequency of 23.0% for both of these mutations (8.0% for -71 and 15.0% for -101). Heterozygotes for either of these two mutations have an overlapping level of Hb A2 ranging from 3.1-3.9% (3.7 ± 0.3) with some cases displaying microcytic and hypochromic anemia, mainly attributed to coinherited defective α-thal genes. Interestingly, each of these mutations were discovered in combination with the sickle cell allele displaying distinct high performance liquid chromatography (HPLC) profiles, different from those observed in the typical sickle cell disease or the sickle cell trait conditions. These investigations are invaluable to provide appropriate counseling for partners undergoing premarital counseling and to understand the molecular basis of mild and atypical forms of sickle cell disease.

Unresolved laboratory issues of the heterozygous state of β-thalassemia: a literature review

“…Of 37 studies regarding factors affecting RBC indices, 67.6% (n=25) identified silent or mild β-thalassemia carriers with normal or marginal MCV and/or MCH. Of 25 studies, 6 (24%) originated from Italy, 6 , 22-26 5 (20%) from India, 14 , 27-30 4 (16%) from China, 31-34 2 (8%) each from Thailand, 35 , 36 Iran 37 , 38 and Pakistan, 39 , 40 one (4%) each from Turkey, 41 Bahrain, 42 Malaysia, 43 and Spain. 44 Silent or mild β-thalassemia mutations reported from different countries are listed in Table 1 .…”

“…Eighteen studies that used 3.5% as the cut-off include five from China, 18 , 21 , 32 , 34 , 70 five from Iran, 15 , 16 , 37 , 47 , 67 two from Thailand, 46 , 53 one each from India, 51 Bangladesh, 20 Saudi Arabia, 19 Portugal, 59 the UAE, 61 and the UK. 52 Similarly, 12 studies that used 4.0% as the cut-off include four from India, 7 , 17 , 27 , 48 four from Thailand, 35 , 49 , 51 , 55 and one each from Malaysia, 43 Bahrain, 42 Italy, 24 and the Netherlands. 73 A 3.9% cut-off was used for three studies from India (n=2) 68 , 71 and Italy (n=1).…”

HbS/β+ thalassemia: Really a mild disease? A National survey from the AIEOP Sickle Cell Disease Study Group with genotype‐phenotype correlation

“…Mutations of the HBB gene interfering with the transcription, RNA cleavage, or mRNA splicing are associated with a β+ phenotype. Among these, mutations in the promoter region have been reported to associate with a very mild phenotype, and some of them are typical of subjects of African descent . To the other end of the spectrum, some splice‐site mutations of the HBB gene, such as the β+ IVS‐I‐110, have been associated with a severe phenotype, both in the homozygous state of thalassemia patients, as well as when co‐inherited with the S mutation .…”

“…Among these, mutations in the promoter region have been reported to associate with a very mild phenotype, and some of them are typical of subjects of African descent. 8,36 To the other end of the spectrum, some splice-site mutations of the (Table 2) with some different phenotypic expression. Severe events occurred in the prediagnosis phase (Table 1); furthermore, sepsis was the event ASS is a medical emergency, and it has been reported as the first severe event in 13.6% of HbSS/β° patients in a pediatric cohort.…”