Red blood cell (RBC) membranopathies, caused by genetic alterations in membrane and cytoskeletal proteins, lead to significant variability in clinical presentation. This study analyzes 23 single nucleotide variants across nine genes (ADD1, ADD2, ANK1, EPB41, PIEZO1, SLC4A1, SPTA1, SPTB, and TAF3) in 225 Mexican patients with suspected RBC membranopathies and their effects on hematological parameters. Key variants, such as ADD2:c.1797C>T, SPTA1:c.5992G>C, SPTA1:c.6046C>A and SPTA1:c.6531-12C>T, were significantly associated with decreased RBC count, hemoglobin levels, packed cell volume, mean corpuscular hemoglobin and/or mean corpuscular hemoglobin concentration. Additionally, the following six combinations showed significant associations with two or three hematological parameters: SPTA1:c.5992G>C + SPTA1:c.6046C>A, SPTA1:c.5992G>C + ADD1:c.1378G>T, ADD1:c.1378G>T + ADD2:c.1797C>T, ADD1:c.1378G>T + PIEZO1:c.6793A>G, ADD2:c.1797C>T + PIEZO1:c.6793A>G, and TAF3:c.410-2550A>G + SPTA1:c.6531-12C>T. These findings underscore the importance of selected population genetic studies to increase our understanding of genotype–hematological phenotype relationships in RBC membranopathies.
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