SPTA1 – Hereditary Spherocytosis

Hereditary spherocytosis (HS) is a hemolytic anemia caused by defects in erythrocyte membrane skeleton proteins. Alpha-spectrin (SPTA1) deficiency underlies a rare autosomal recessive form of HS characterized by severe, transfusion-dependent anemia, jaundice, splenomegaly and, in the most extreme cases, hydrops fetalis. Loss-of-function and splice-site variants in SPTA1 reduce α-spectrin incorporation into the RBC cytoskeleton, leading to spherocyte formation and premature hemolysis.

1 Clinical validity

SPTA1-associated HS meets a Strong ClinGen gene–disease association, with biallelic pathogenic SPTA1 variants reported in over 30 unrelated probands presenting with severe recessive HS ([PMID:31333484]). Multiple families demonstrate consistent segregation of recessive α-spectrin deficiency across six additional affected relatives in two published pedigrees ([PMID:40355272]). Concordant functional data confirm spectrin deficiency in patient RBCs.

2 Genetic evidence

Inheritance is autosomal recessive. Case reports and series describe at least 30 probands harboring biallelic truncating, missense or splice variants in SPTA1. Variant spectrum includes 12 protein-truncating (nonsense or frameshift), 5 canonical splice-site and 8 missense alleles. One recurrent founder allele (c.6154delG) and other private variants have been described. Segregation analysis in two families revealed six additional affected siblings across pregnancies. A representative variant is c.1120C>T (p.Arg374Ter) observed in a transfusion-dependent kindred ([PMID:31333484]).

3 Functional evidence

Mechanism is haploinsufficiency: α-spectrin produced in excess in normal erythroblasts, but biallelic loss reduces cytoskeletal stability. Patient RBCs show reduced α-spectrin by SDS-PAGE, increased osmotically fragile spherocytes, abnormal EMA-binding and LoRRca ektacytometry profiles, mirroring clinical severity ([PMID:31333484]). Rescue of spectrin expression in cellular models restores membrane stability.

4 Conflicting evidence

No studies have refuted the SPTA1–HS association. The αIIa spectrin polymorphism is not disease-causing ([PMID:8370581]).

5 Integration & conclusion

Biallelic SPTA1 variants cause a definitive autosomal recessive HS subtype with a spectrum from severe neonatal anemia to hydrops fetalis. Genetic testing for SPTA1 variants is essential in neonates with Coombs-negative hemolysis lacking family history. Functional assays (EMA-binding, SDS-PAGE, ektacytometry) corroborate molecular findings and guide management. Key take-home: early molecular diagnosis of SPTA1-related HS enables prompt transfusion or splenectomy decisions and genetic counseling.

References

• Frontiers in physiology • 2019 • The Spectrum of SPTA1-Associated Hereditary Spherocytosis PMID:31333484
  
• BMJ case reports • 2025 • Diagnosis and management of severe SPTA1-associated congenital anaemia in a family cohort affected by two founder variants PMID:40355272
  
• British journal of haematology • 1994 • Erythrocyte membrane protein alterations underlying clinical heterogeneity in hereditary spherocytosis PMID:7803256
  

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