source: The American Society of Pediatric Hematology/Oncology

year: 2016

authors: Yasser A. Wali, Shahina Daar, Maha Alwaidy, Taimoora S. Al Subhi, Aisha ElKhayat, Shoaib AlZadjali, Aisha AlHosni, Heba Omar, Halima AlBalushi, Abdulhakim Al-rawas, Mohamed Elshinawy

Background: Hemoglobin SOman results from double mutations in the β globin chain; the classic βS mutation (β6 Glu→Val), and a second mutation in the same chain (β121 Glu→Lys) identical to that of HbOArab. In the literature only 6 carriers have been described. HbS-Oman carriers can have severe clinical presentation matching sickle cell disease with frequent vaso-occlusive crises, acute chest syndrome and even cerebrovascular accidents.

Objectives: Study the clinical phenotype, genotype and cell biology of both carriers of HbSOman and compound heterozygotes HbS-SOman.

Design/Method: A cross sectional study that includes all identified carriers of HbSOman and compound heterozygotes. Demographic and clinical phenotype data were collected, including family pedigrees that were tracked to the same grandmother indicating a founder effect. Hematological parameters and HPLC were performed. β-globin chain haplotypes were done using RFLP. Next generation Exom sequencing for α-globin gene non-deletional mutations, β-gene mutations and other genetic modifiers including AHSP, BCL11a, KLF1, TAL1 and GATA1 was performed. Deletional α-thalassemia mutations were identified using α-gene scan. Samples were processed for non-electrolytic hemolysis test, K+ efflux by using radioactive tracer studies.

Results: We identified 53 carriers, 27 males and 26 females and 6 HbS-SOman patients, 4 males and 2 females, age range between 2-75 years. Hemoglobin range was 7.5-14.7 g/dl (11.9+1.6), and SOman 9.5-25.3% (15.9+3.7) for carriers, while Hb ranged from 3.2-7.8 g/dl (5.2+2.4) and SOman 6-24.6% (11.6+6.6) for compound heterozygotes. Clinical severity index correlated with the SOman percent in the carriers with a cut-off value of 14% and with decreased production of α-chains due to deletional or non-deletional mutations; however, there were no such correlations in the compound heterozygotes who presented in early infancy with severe transfusion-dependence. Other genetic modifiers seem to have no effect. Activation of a deoxygenation-induced Cl–independent K+flux, i.e. Psickle-like permeability, a lack of Gardos channel activity and minimal activity of potassium chloride co-transporter was found in SOman carriers.

Conclusion: HbSOman is a severe form of SCD; carriers can be severely symptomatic and compound heterozygotes present as thalassemia major with early transfusion dependence. Alpha thalassemia mutation is the main genetic modifier in carriers. SOman cells have increased sickling and hemolytic characteristics.

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