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Condition report · Hematological

Hereditary Spherocytosis

Whole genome sequencing evaluates all five hereditary spherocytosis genes (ANK1, SLC4A1, SPTB, EPB41, and EPB42), providing the molecular diagnosis that predicts disease severity and guides the splenectomy decision.

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About this condition

A genetic disorder characterized by sphere-shaped red blood cells that are fragile and prematurely destroyed, leading to hemolytic anemia.

Hereditary spherocytosis (HS) is the most common inherited hemolytic anemia in populations of Northern European descent, with a prevalence of approximately 1 in 2,000-5,000. HS is caused by pathogenic variants in genes encoding red blood cell membrane skeleton proteins: ANK1 (ankyrin-1, ~40-65% of cases), SLC4A1 (band 3/AE1, ~15-25%), SPTB (β-spectrin, ~15-30%), EPB41 (protein 4.1), and EPB42 (protein 4.2). These structural protein deficiencies weaken the vertical connections between the lipid bilayer and the underlying spectrin-actin skeleton, causing progressive membrane vesiculation that transforms the normally biconcave disc-shaped red cell into a spherocyte.

Spherocytes are less deformable than normal red cells and cannot traverse the splenic sinusoidal slits; they are selectively trapped and destroyed in the spleen, producing chronic extravascular hemolysis. Clinical severity ranges from compensated hemolysis (mild anemia, reticulocytosis, indirect hyperbilirubinemia) to transfusion-dependent severe anemia. Complications include chronic jaundice, pigment gallstones (often requiring cholecystectomy by early adulthood), aplastic crises triggered by parvovirus B19 infection, and splenomegaly. HS is often diagnosed in childhood during evaluation for anemia, jaundice, or an incidentally discovered enlarged spleen.

Splenectomy eliminates the site of spherocyte destruction and effectively cures the hemolytic anemia, but carries lifelong infection risk from encapsulated organisms (Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae), requiring pre-splenectomy vaccination, post-splenectomy antibiotic prophylaxis, and patient education about overwhelming post-splenectomy infection (OPSI). The decision to proceed with splenectomy depends heavily on disease severity. ANK1 variants tend to cause moderate-to-severe HS more frequently, while SLC4A1 variants more often cause mild disease. Molecular genotyping provides prognostic information that supplements the clinical severity assessment.

Parvovirus B19 infection causes aplastic crisis in HS patients: red cell production ceases for 7-10 days, dropping hemoglobin precipitously. This is a medical emergency in patients with chronic hemolysis who depend on high reticulocyte production.

The condition we analyse

Hereditary spherocytosis is a congenital hemolytic anemia with a wide clinical spectrum (from symptom-free carriers to severe hemolysis) characterized by anemia, variable jaundice, splenomegaly and cholelithiasis.

What a diagnosis changes

Folic acid supplementation; splenectomy for moderate-severe disease (partial or total); pre-splenectomy vaccination; cholecystectomy for gallstones; transfusion support during aplastic crises; monitoring for parvovirus B19

Genes analysed

Also known as

congenital spherocytic hemolytic anaemia; congenital spherocytosis; Minkowski-Chauffard disease; spherocytic anaemia

Includes 5 related subtypes ↓
  • hereditary spherocytosis type 1
  • hereditary spherocytosis type 2
  • hereditary spherocytosis type 3
  • hereditary spherocytosis type 4
  • hereditary spherocytosis type 5
MONDO:0019350Orphanet 822MedGen 52450

Why whole genome sequencing

Osmotic fragility testing diagnoses HS but does not identify which gene is affected. The specific gene predicts disease trajectory and informs whether splenectomy will be needed, critical for surgical counseling in childhood.

ANK1 variants predict more severe disease: knowing the gene guides the splenectomy decision timeline

ANK1 pathogenic variants are associated with moderate-to-severe HS more frequently than SLC4A1 or SPTB variants. For a child newly diagnosed with HS who currently has compensated hemolysis, knowing whether the causative variant is in ANK1 or SLC4A1 provides prognostic information: ANK1-associated disease is more likely to require splenectomy by adolescence, while SLC4A1-associated disease may remain manageable with folic acid supplementation and observation alone. This genotype-severity correlation supplements clinical monitoring and helps families plan.

HS can be confused with autoimmune hemolytic anemia: molecular diagnosis prevents inappropriate immunosuppressive therapy

Hereditary spherocytosis and warm autoimmune hemolytic anemia (AIHA) both present with spherocytes on the peripheral blood smear, elevated indirect bilirubin, and reticulocytosis. The treatments are entirely different: HS requires splenectomy for severe disease; AIHA requires corticosteroids and immunosuppression. The direct antiglobulin test (DAT/Coombs test) usually distinguishes them, but can be equivocal. Molecular confirmation of an HS-causing variant in ANK1, SLC4A1, or SPTB definitively establishes the diagnosis as inherited membrane disease, eliminating autoimmune hemolysis from the differential and preventing inappropriate immunosuppressive treatment.

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