Journal Article

Control of fetal hemoglobin: new insights emerging from genomics and clinical implications

Swee Lay Thein, Stephan Menzel, Mark Lathrop and Chad Garner

in Human Molecular Genetics

Volume 18, issue R2, pages R216-R223
Published in print October 2009 | ISSN: 0964-6906
Published online October 2009 | e-ISSN: 1460-2083 | DOI:
Control of fetal hemoglobin: new insights emerging from genomics and clinical implications

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Increased levels of fetal hemoglobin (HbF, α2γ2) are of no consequence in healthy adults, but confer major clinical benefits in patients with sickle cell anemia (SCA) and β thalassemia, diseases that represent major public health problems. Inter-individual HbF variation is largely genetically controlled, with one extreme caused by mutations involving the β globin gene (HBB) complex, historically referred to as pancellular hereditary persistence of fetal hemoglobin (HPFH). These Mendelian forms of HPFH are rare and do not explain the common form of heterocellular HPFH which represents the upper tail of normal HbF variation, and is clearly inherited as a quantitative genetic trait. Genetic studies have identified three major quantitative trait loci (QTLs) (Xmn1-HBG2, HBS1L-MYB intergenic region on chromosome 6q23, and BCL11A on chromosome 2p16) that account for 20–50% of the common variation in HbF levels in patients with SCA and β thalassemia, and in healthy adults. Two of the major QTLs include oncogenes, emphasizing the importance of cell proliferation and differentiation as an important contribution to the HbF phenotype. The review traces the story of HbF quantitative genetics that uncannily mirrors the changing focus in genetic methodology, from candidate genes through positional cloning, to genome-wide association, that have expedited the dissection of the genetic architecture underlying HbF variability. These genetic results have already provided remarkable insights into molecular mechanisms that underlie the hemoglobin ‘switch’.

Journal Article.  4848 words.  Illustrated.

Subjects: Genetics and Genomics

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