SPTA1 – Hereditary Pyropoikilocytosis

Hereditary pyropoikilocytosis (HPP) is a rare, autosomal recessive hemolytic anemia characterized by extreme poikilocytosis, microspherocytes, and cell fragmentation due to destabilized erythrocyte membranes. Biallelic variants in SPTA1 (alpha-spectrin) disrupt spectrin self-association or reduce spectrin expression, leading to membrane instability and severe hemolysis. This gene–disease association is supported by multiple unrelated probands, segregation within multi-generation pedigrees, and concordant functional assays demonstrating defective spectrin tetramer formation.

Genetic evidence for HPP includes compound heterozygous and homozygous SPTA1 variants identified in neonatal and fetal cases. A de novo homozygous frameshift mutation c.6154del (p.Ala2052LeufsTer4) was reported in a fetus presenting with profound anemia and hydrops fetalis managed by intrauterine transfusions (PMID:38031483). Neonatal case reports describe compound heterozygosity for the missense variant c.83G>A (p.Arg28His) in trans with the αLELY low-expression polymorphism presenting with severe jaundice and hemolytic anemia (PMID:36278520).

Segregation analyses in a white French family over four generations demonstrated heterozygosity for the SPTA1 c.64G>A (p.Glu22Lys) variant in eight affected relatives with clinical expression ranging from hereditary elliptocytosis to HPP, correlating with variant spectrin content (PMID:2328319). Additional functional studies in nine individuals from five families confirmed a second variant, c.620T>C (p.Leu207Pro), segregating with the abnormal spectrin alpha I/46-50a peptide and HPP phenotype (PMID:1541680).

Functional assessments reveal that pathogenic SPTA1 variants impair spectrin dimer-dimer self-association, leading to increased unassembled spectrin dimers above a threshold of 40–50% and consequent membrane fragility. In vitro dimer self-association assays in over 100 patients correlate the severity of spectrin tetramerization defects with clinical hemolysis and require >50% Sp dimer for severe phenotypes (PMID:8136282).

No studies have conclusively refuted the SPTA1–HPP association, and no significant allelic heterogeneity conflicts have been reported. The cumulative evidence meets ClinGen criteria for a Strong gene–disease association, with robust genetic and experimental corroboration.

Key take-home: Confirmation of biallelic SPTA1 variants enables molecular diagnosis of HPP, informs prognosis, guides perinatal management, and supports genetic counseling.

References

• Transfusion • 2024 • Homozygous SPTA1-associated hereditary pyropoikilocytosis presenting as hydrops fetalis. PMID:38031483
• Blood • 1990 • Hereditary pyropoikilocytosis and elliptocytosis in a white French family with the spectrin alpha I/74 variant related to a CGT to CAT codon change (Arg to His) at position 22 of the spectrin alpha I domain. PMID:2328319
• The Journal of clinical investigation • 1992 • A common type of the spectrin alpha I 46-50a-kD peptide abnormality in hereditary elliptocytosis and pyropoikilocytosis is associated with a mutation distant from the proteolytic cleavage site. Evidence for the functional importance of the triple helical model of spectrin. PMID:1541680
• British journal of haematology • 1993 • Molecular basis of clinical and morphological heterogeneity in hereditary elliptocytosis (HE) with spectrin alpha I variants. PMID:8136282

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