A Variable Clinical Presentation of Hemoglobin City of Hope

Hemoglobin City of Hope (Hb-COH), NC_000011.9(NM_000518.5):c.208G > A; NP_000509.1:p.(Gly70Ser), has rarely been described. The presentation ranges from asymptomatic heterozygosity to significant anemia in patients carrying an additional pathogenic variant in β-globin. To elucidate the clinical spectrum of Hb-COH, we analyzed 31 individuals carrying the variant, including, for the first time, homozygous individuals. Seven patients who were compound heterozygous for Hb-COH and an additional variant in β-globin, presented with mild-to-severe microcytic anemia and elevated hemoglobin-A2. Three (43%) of these also had elevated fetal hemoglobin, but none required blood transfusions. Seven patients coinherited Hb-COH with an -α -deletion (NG_000006.1:g.34247_38050del), their presentation ranged from mild microcytic anemia to normal blood counts. Three homozygous and 14 heterozygous individuals for Hb-COH had normal blood counts. Most Hb-COH alleles whose origin was traceable were from Ashkenazi Jews (70.4%). To conclude, while isolated Hb-COH appears asymptomatic even in the homozygous state, it may cause significant anemia when coinherited with an additional pathogenic variant in β-globin. Understanding the full impact of Hb-COH is crucial for optimal patient management and for genetic counseling.