HBB was first reported in relation to autosomal dominant unstable hemoglobin disease in 1962 (Frick et al. 1962, PMID: 13895148). Unstable hemoglobin disease results from the presence of a structurally abnormal hemoglobin variant which leads to Heinz bodies or basophilic inclusions in the red blood cells. The disease is characterized by hemolytic anemia, heat-labile hemoglobin, and is sometimes accompanied by splenomegaly and jaundice. The clinical severity and presentation of the unstable hemoglobinopathies vary widely. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms, inheritance pattern, and phenotypic variability in unstable hemoglobin disease and other disease entities associated with HBB. Therefore, the following disease entities have been split into multiple disease entities: AD familial erythrocytosis 7, AD and AR alpha-thalassemia, AD hemoglobin M disease, AD unstable hemoglobin disease, and AR Sickle cell disease. This curation addresses HBB in relation to AD unstable hemoglobin disease. At least 14 unique missense variants that have been reported in 15 probands in 14 publications (PMIDs: 13895148, 6771953, 6877904, 3781864, 8330973, 9730372, 11920235, 29573049, 25347256, 20730880, 30032685, 32029504, 33613322, 37457725) are included in this curation. Eight were reported as de novo occurrences. This gene disease association is also supported by experimental evidence including expression pattern of HBB across human tissues which is highly specific within whole blood (PMID: 23715323), biochemical studies indicating the well-established function of HBB in oxygen binding (PMID: 11747442), and its protein-protein interaction with the alpha hemoglobin chain encoded by HBA1 and HBA2 genes (PMID: 6644819), which harbors variants associated with unstable hemoglobin disease. Additionally, an ENU-induced mouse model replicated the human phenotype (PMIDs: 28304246). In summary, there is definitive evidence supporting the relationship between HBB and autosomal dominant unstable hemoglobin disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen General Gene Curation Expert Panel on 2/28/2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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