Fetal hemoglobin (HbF) levels vary considerably in healthy normal adults. The distribution of HbF and F cells, erythrocytes that contain measurable HbF, in healthy adults is continuous, although most adults have HbF of less than 0.6% of total ... Fetal hemoglobin (HbF) levels vary considerably in healthy normal adults. The distribution of HbF and F cells, erythrocytes that contain measurable HbF, in healthy adults is continuous, although most adults have HbF of less than 0.6% of total Hb. Approximately 10 to 15% of individuals have increases of HbF ranging from 0.8% to 5%, a trait often referred to as hereditary persistence of fetal hemoglobin (HPFH), usually distributed unevenly among red cells. When coinherited with beta-thalassemia (see 613985) or sickle cell anemia (603903), HPFH can increase HbF output to levels that are clinically beneficial (Thein et al., 2007). For a general phenotypic description and a discussion of loci that may affect fetal hemoglobin levels, see HBFQTL1 (141749).
Thein et al. (1994) reported a large family from the state of Gujarat in India in which members had beta-thalassemia and/or hereditary persistence of fetal hemoglobin. The presence of HbF-containing cells segregated as an independent trait from the ... Thein et al. (1994) reported a large family from the state of Gujarat in India in which members had beta-thalassemia and/or hereditary persistence of fetal hemoglobin. The presence of HbF-containing cells segregated as an independent trait from the beta-thalassemia. The proband had homozygous beta-thalassemia, but had a mild phenotype associated with high circulating levels of HbF. He married an unrelated woman with heterozygous beta-thalassemia. Two sons were homozygous for beta-thalassemia, but did not inherit HPFH from the father, as manifest by their severe disease. A detailed examination of the rest of the large kindred showed that many members had increased HbF at 0.8 to 3.4%, and that those heterozygous for beta-thalassemia had HbF levels ranging from 2.5 to 24%. F-cell levels ranged from 5.8 to 26%, consistent with a heterocellular form of HPFH.
Pandit et al. (2008) provided evidence suggesting that a 32C-T SNP in the 5-prime untranslated region of the HBS1L gene (dbSNP rs2297339) may influence HbF. The C allele was associated with increased HbF levels among Thai-Chinese patients with ... Pandit et al. (2008) provided evidence suggesting that a 32C-T SNP in the 5-prime untranslated region of the HBS1L gene (dbSNP rs2297339) may influence HbF. The C allele was associated with increased HbF levels among Thai-Chinese patients with beta-thalassemia, particularly among those who were heterozygous for the HBG2 polymorphism (142250.0028). dbSNP rs2297339 in HBS1L is predicted to confer a binding site for transcription factor AP4 (600743) and may influence gene expression. Wahlberg et al. (2009) found 3 sites in the core intergenic HMIP2 block that were hypersensitive to DNase I cleavage, indicative of active chromatin, in erythroid cell lines. Chromatin immunoprecipitation with microarray (ChIP-chip) analysis showed strong histone acetylation in a 65-kb interval encompassing the HMIP2 and HMIP3 blocks in primary human erythroid cells, but not in non-MYB-expressing HeLa cells. Several potential cis-regulatory elements and strong GATA1 (305371) signals were identified in this area. The findings suggested that this region contains distal regulatory sequences that could be important in hematopoiesis by controlling MYB expression. To establish the identity of the gene at the HBS1L-MYB locus that influences HbF levels, Galarneau et al. (2010) resequenced 70 individuals with sickle cell anemia and identified 6 and 4 rare missense variants in HBS1L and MYB, respectively. They genotyped these variants in 1,032 individuals with sickle cell anemia to assess their burden at the gene level by comparing normalized HbF levels in carriers and noncarriers. Results for HBS1L were not significant; however, a significant difference was observed for MYB (corrected p = 0.005), with the 25 carriers having on average 1.4% more HbF than the 937 noncarriers. These data suggested that MYB is the gene causally involved in controlling HbF production at the HBFQTL2 locus.