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The autosomal dominant red blood cell membranopathy Hereditary Elliptocytosis is caused primarily by variants in SPTA1, which encodes erythrocyte alpha-spectrin. Clinical studies spanning over three decades have identified more than 113 unrelated affected individuals from 61 families, demonstrating segregation of SPTA1 variants with elliptocytosis and hemolytic anemia (PMID:8136282).
Genetic evidence includes recurrent and private missense and splice variants in SPTA1. The prototypical founder variant c.779T>C (p.Leu260Pro) has been observed in multiple kindreds, notably in Brazilian and Calabrian populations, where heterozygotes manifest mild to moderate elliptocytosis (PMID:9691144). Case reports describe additional novel heterozygous mutations (e.g., c.86A>C (p.Gln29Pro)) with variable expressivity and incomplete penetrance, confirming autosomal dominant inheritance.
Functional assays have demonstrated that pathogenic SPTA1 variants disrupt spectrin dimer self-association, leading to increased proportions of unassembled dimers above the critical 40–50% threshold associated with severe hemolysis and requirement for splenectomy (PMID:8136282). Biophysical and proteomic analyses of p.Leu260Pro erythrocytes revealed altered membrane curvature, increased rigidity, abnormal lipid domain composition, and impaired Ca2+ exchange, directly linking molecular defect to cellular phenotype (PMID:32751168).
Collectively, the breadth of segregating families, diverse variant spectrum, and concordant functional data meet criteria for a ClinGen Definitive gene–disease association. Genetic evidence is classified as Strong due to multiple variant classes in over 100 probands with clear segregation, and functional evidence is Strong given consistent mechanistic studies demonstrating pathogenic impact on spectrin assembly and membrane integrity.
Key Take-home: SPTA1 variant analysis, notably including c.779T>C (p.Leu260Pro), is essential for diagnosing hereditary elliptocytosis and guiding clinical management, including monitoring for hemolysis severity and splenectomy consideration.
Gene–Disease AssociationDefinitiveOver 113 unrelated probands across 61 families with segregation and concordant functional studies Genetic EvidenceStrongMultiple variant classes in over 100 probands with autosomal dominant inheritance and clear family segregation Functional EvidenceStrongIn vitro and biophysical assays demonstrate impaired spectrin self-association and membrane defects |