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J.Z. Xu et al.
Non-Mendelian inheritance of HbS
Homozygosity due to uniparental disomy of chromo- some 11 is another rare genetic defect. Two individuals were reported to have inherited HbS from one parent and normal HbA from the other parent but presented later in life with phenotypic SCD. In-depth DNA analysis revealed that post-zygotic mitotic recombination had occurred, leading to mosaic segmental isodisomy.57,58 These individuals had dual populations of HbSS and HbAS erythroid progenitors and peripheral red blood cells, with HbSS erythrocytes accounting for the chronic hemolytic phenotype of SCD.
These cases demonstrate that the diagnosis of sickle trait can be nuanced and deserves further workup if the individual has a phenotype of SCD. In such diagnostically challenging scenarios, family studies are extremely useful, and detailed hemoglobin evaluation is essential (Figure 2). A relative excess of HbA over HbS with no other Hb vari- ant present indicates that only one copy of abnormal
allele is present. If phenotypic and genetic workup both show HbAS, a search for modifiers that promote HbS polymerization should be undertaken.
Conclusion
While HbAS represents an asymptomatic carrier state, clinical and epidemiological studies have shown that SCT is certainly not an entirely harmless condition. The presence of HbS in SCT may contribute to specific dis- ease processes, particularly under extreme conditions that promote HbS polymerization. Additionally, individ- uals with HbAS can present with complications typical of the SCD phenotype. Such cases of unusually severe HbAS can pose a diagnostic challenge, but elucidating their molecular basis provides further insight into the pathophysiology of SCD and help to identify genetic risk modifiers in SCT.
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