Mutations of spectrin (Sp) involving the Sp heterodimer self-association site (the I domain of Sp) represent the most common group of membrane skeletal defects in hereditary elliptocytosis (HE) and a closely related disorder, hereditary pyropoikilocytosis (HPP). HPP is characterized by extreme anisocytic microcytosis, a severe spectrin dimer self-association defect and spectrin deficiency. The conventional explanation for the different phenotypes is that HPP subjects are compound heterozygotes for an sp defect that interferes with sp tetramer assembly and a second defect which results in decreased synthesis of functional sp. In contrast, HE subjects have normal spectrin content and a less severe sp self-association defect. The clinical expression of HE/HPP is influenced by the inheritance of modifying factors such as the Sp hypomorphic mutation, LELY. LELY is a low expression allele of the Sp gene characterized by a C>G mutation in codon 1857 of exon 40 and a C>T -12 mutation in intron 45 that is responsible for partial skipping of exon 46, which is essential for the functional assembly of /b sp dimers.