IthaID: 2127

Context nucleotide sequence:
CAACCCATGGGTGGAGTTTAGCCAGG [C/T] ACCGTTTCAGACAGATATTTGCATT (Strand: -)

Also known as: XmnI, rs7482144

Comments: Xmn1-Gγ site is common in all population groups and is present at a frequency of 0.32–0.35. Xmn1-Gγ does not always raise the Hb F levels in otherwise normal individuals. Under conditions of haemopoietic stress, for example in homozygous β-thalassaemia and sickle cell disease, presence of the Xmn1-Gγ site favours a higher Hb F response. The presence of the XmnI T/T genotype correlates strongly in response to hydroxyurea treatment in transfusion-dependent β-thal patients. SNP associated with F-cell variation in healthy Northern Europeans (TwinsUK cohort; n=269 and n=775 in two independent studies). It associated with HbF levels in the Cooperative Study of Sickle Cell Disease (CSSCD; n=1518 and n=1275 in two independent studies) and a Brazilian sickle cell disease (SCD) study sample (n=167). It associated with HbF levels and F-cell numbers in a Hong Kong Chinese sample heterozygous for the β-thalassemia mutation (n=241). It associated with HbF levels and disease severity in a study sample of Thai patients with HbE/β0-thalassemia, who were classified as clinically mild (n=207) or severe (n=305) for the disease. It associated with HbF levels in Portuguese β-thal carriers. It had a modifying effect on HbF and clinical score in Indonesian HbE/β-thal patients. The XmnI T allele associated with elevated HbF in Thai individuals with homozygous HbE (n=115), as well as with high Gγ expression in patients with SCD (Georgia, Turkey, Surinam and Saudi Arabia) and β-thalassemia (Georgia, Algeria and Sicily). The association with HbF was not replicated in SCD patients from Cameroon (n=596) and Tanzania (n=222) [PMID: 33073380]. SNP associated with significantly more pain events in young patients with SCA (BABY HUG cohort) [PMID: 23606168]. SNP associated with good response to HU treatment in terms of Hb levels and blood transfusion dependency both in β-thalassaemia and sickle cell disease cohorts [PMID: 17880608, 14722738, 15477200, 25263325]. Associated with HbF levels and gamma chains ratio (Gγ:Αγ) in an Angolan pediatric population with sickle cell anaemia [PMID: 34069401]. Associated with a robust effect on HbF levels (mean = 16.7±2.1%) in Kuwaiti patients with SCD [PMID: 34204365]. Reported to lead to 2-4% of HbF in heterozygous carriers. Disruption of the -158 binding site via CRISPR-Cas9 induced HbF expression in adult HUDEP-2 erythroid cells [PMID: 32917636]. It identifies the polymorphic site XmnI in the beta-globin gene cluster, which is used in the characterization of βS haplotypes (Benin, Bantu, Senegal, Cameroon, Arab-Indian).

We follow the HGVS sequence variant nomenclature and IUPAC standards.

Heterozygous records (preview in IthaPhen)

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20. He Y, Lin W, Luo J, Influences of genetic variation on fetal hemoglobin., Pediatr Hematol Oncol , 28(8), 708-17, 2011 PubMed
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22. Akinsheye I, Solovieff N, Ngo D, Malek A, Sebastiani P, Steinberg MH, Chui DH, Fetal hemoglobin in sickle cell anemia: molecular characterization of the unusually high fetal hemoglobin phenotype in African Americans., Am J Hematol, 87(2), 217-9, 2012 PubMed
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26. Wonkam A, Ngo Bitoungui VJ, Vorster AA, Ramesar R, Cooper RS, Tayo B, Lettre G, Ngogang J, Association of variants at BCL11A and HBS1L-MYB with hemoglobin F and hospitalization rates among sickle cell patients in Cameroon., PLoS ONE , 9(3), e92506, 2014 PubMed
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28. Pereira C, Relvas L, Bento C, Abade A, Ribeiro ML, Manco L, Polymorphic variations influencing fetal hemoglobin levels: association study in beta-thalassemia carriers and in normal individuals of Portuguese origin., Blood Cells Mol. Dis. , 54(4), 315-20, 2015 PubMed
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31. Rujito L, Basalamah M, Siswandari W, Setyono J, Wulandari G, Mulatsih S, Sofro AS, Sadewa AH, Sutaryo S, Modifying effect of XmnI, BCL11A, and HBS1L-MYB on clinical appearances: A study on β-thalassemia and hemoglobin E/β-thalassemia patients in Indonesia., Hematol Oncol Stem Cell Ther , 9(2), 55-63, 2016 PubMed
32. Shaikho EM, Farrell JJ, Alsultan A, Qutub H, Al-Ali AK, Figueiredo MS, Chui DHK, Farrer LA, Murphy GJ, Mostoslavsky G, Sebastiani P, Steinberg MH, A phased SNP-based classification of sickle cell anemia HBB haplotypes., BMC Genomics, 18(1), 608, 2017 PubMed
33. Weber L, Frati G, Felix T, Hardouin G, Casini A, Wollenschlaeger C, Meneghini V, Masson C, De Cian A, Chalumeau A, Mavilio F, Amendola M, Andre-Schmutz I, Cereseto A, El Nemer W, Concordet JP, Giovannangeli C, Cavazzana M, Miccio A, Editing a γ-globin repressor binding site restores fetal hemoglobin synthesis and corrects the sickle cell disease phenotype., Sci Adv . , 6(7), 0, 2020 PubMed
34. Delgadinho M, Ginete C, Santos B, Miranda A, Brito M, Genotypic Diversity among Angolan Children with Sickle Cell Anemia., Int J Environ Res Public Health, 18(10), 0, 2021 PubMed
35. Akbulut-Jeradi N, Fernandez MJ, Al Khaldi R, Sukumaran J, Adekile A, Unique Polymorphisms at , and Loci Associated with HbF in Kuwaiti Patients with Sickle Cell Disease., J Pers Med, 11(6), , 2021 PubMed