Genetic Background of the Sickle Cell Disease Pediatric Population of Dakar, Senegal, and Characterization of a Novel Frameshift β-Thalassemia Mutation [HBB: c.265_266del; p.Leu89Glufs*2]

Abstract

Sickle cell disease is a genetic disorder with a large variability in the pattern and severity of clinical manifestations. Different genetic modulators have been identified but very few epidemiologic data are available on these modifier genes in Senegal. This study aimed to determine their prevalence in a Senegalese sickle cell disease pediatric population. The following genetic parameters were genotyped in 295 sickle cell disease children of the Dakar pediatric hospital: sickle cell disease genotype [β/β (HBB: c.20A>T), β/β (HBB: c.19G>A), β/β-thalassemia (β-thal)], XmnI polymorphism, the five most common α-thalassemia (α-thal) deletions and the A(-) and Betica glucose-6-phosphate-dehydrogenase (G6PD) deficient variants. Despite very few β/β and β/β-thal children (1.0% each), a novel frameshift β-thal mutation was characterized: HBB: c.265_266del; p.Leu89Glufs*2. The -α (rightward) deletion was the only α-thal deletion identified in this cohort (12.0% allelic frequency). Most of β/β patients (61.9%) were homozygous for the XmnI polymorphism and assumed to carry a Senegal/Senegal β haplotype. The remaining haplotypes were predominantly of the Benin type. While the Betica G6PD variant was quite frequent (13.0%), a low frequency of the A(-) variant was detected (1.0-2.0%). The systematic genotyping of the -α deletion and of the G6PD Betica variant in sickle cell disease patients from Senegal could be useful to identify patients at risk for several complications, such as cerebral vasculopathy, where it has been demonstrated that a normal α-globin genotype and G6PD deficiency are predisposing factors. These patients should be eligible for a transcranial Doppler examination that is not routinely offered in Senegal.

Cell‐derived microparticles and sickle cell disease chronic vasculopathy in sub‐Saharan Africa: A multinational study

“…As no molecular studies were conducted, it is possible that some of the patients were in fact Sβ 0 ‐thal compound heterozygotes. However, this genotype is very rare among patient with SCD in Senegal and Mali (~1% and ≤4% respectively), 15 and unpublished personal data. Furthermore, most of the authors consider that the pathophysiology of the two genetic conditions is indistinguishable and pool SS and Sβ° patients in one single group of ‘severe SCD’ condition.…”

Combined and differential effects of alpha‐thalassemia and HbF‐quantitative trait loci in Senegalese hydroxyurea‐free children with sickle cell anemia

“…In a previous epidemiological article, we reported the allelic frequencies of alpha‐thalassemia deletions (–3.7 kb, –4.2 kb, –20.5 kb, MED and SEA), G6PD deficiency (Med, A‐ and Betica variants), and XmnI polymorphism in our SCA cohort. For the present study, these data were completed by the genotyping of two other HbF QTL (rs1427407 G > T in intron 2 of the BCL11A gene and rs28384513 A > C in the HMIP region) using in‐house high‐resolution melting protocols on the Light Cycler ® 480 device (Roche Diagnostics, Meylan, France) . A composite HbF QTL score ranging from zero to six and corresponding to the number of HbF‐promoting alleles was calculated with the XmnI , BCL11A , and HMIP genotypes.…”

“…The prevalence and allelic frequencies of all studied genetic parameters are presented in Table . The ‐α 3.7 deletion was the only observed alpha‐thalassemia deletion with a quite low allelic frequency compared to East and South Africa . The A (‐) and Med G6PD ‐deficient variants were very rare or absent while Betica was the most frequent one.…”

“…As discussed above, the first one is the very low number of patients with homozygous alpha‐thalassemia ( n = 7). The very low allelic frequency of alpha‐thalassemia in Senegalese patients with SCA compared to other African countries like Congo, Kenya, Uganda, or Tanzania may be the consequence of a differential survival selection relying on two facts: (1) higher HbF levels and milder SCA clinical phenotypes in Senegal and (2) lower prevalence of Malaria in West Africa compared to subequatorial countries. The second limitation of our study is the relative paucity of the clinical end points since some medical examinations routinely performed in developed countries (like transcranial Doppler of cerebral arteries) are not available in Senegal.…”

Influence of Oxidative Stress Biomarkers and Genetic Polymorphisms on the Clinical Severity of Hydroxyurea-Free Senegalese Children with Sickle Cell Anemia

“…The main alpha-thalassemia deletions (−3.7 Kb, −4.2 Kb, −20.5 Kb, MED and SEA) and G6PD deficient variants (Med, A- and Betica variants) were searched by a multiplex gap-PCR method [ 26 ] and dedicated in-house high resolution melting (HRM) protocols [ 27 , 28 ], respectively. Three HbF QTLs were genotyped: the so-called XmnI polymorphism in the promoter region of the G gamma-globin gene (rs748214; HBG2 :c.-211C > T) and two tag- SNPs in the BCL11A (rs1427407 G > T in intron 2) and HMIP (rs28384513 A > C) loci.…”