Severe Hemolytic Phenotype in Children With Sickle Cell Anemia and Co‐Inherited Red Blood Cell Variants

Remarkable phenotypic variability exists among individuals with sickle cell anemia (SCA), which may be explained by co-inheritance of traits affecting red blood cell (RBC) biology, such as genes affecting globin expression or glucose-6-phosphate dehydrogenase enzyme activity. Here, we describe three children with severe SCA who have co-inherited variants in genes for membrane proteins (SPTA1 and EPB1) and PIEZO1. These cases suggest that variants in RBC membrane proteins may contribute to SCA severity and phenotypic variation. Co-Inheritance of such variants could, in theory, affect outcomes of emerging SCA therapies, including genetic modification treatments.