SCIENTIFIC BACKGROUND

ANK1, EPB42, SLC4A1, SPTA1, SPTB

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Scientific Background

Hereditary spherocytosis (HS) is the most common cause of congenital hemolytic anemia in Caucasians. The prevalence is approximately 1:2,000 to 1:5,000. The molecular cause is a defect in the erythrocyte membrane proteins, which play a central role in the stabilization and organization of the plasma membrane. This leads erythrocytes losing their shape and becoming spherical (spherocytes), as well as to increased membrane permeability, enhanced glycolysis and increased ATP turnover. The spherocytes are removed from the bloodstream early by the spleen.

 

Hereditary spherocytosis is a clinically, biochemically and genetically heterogeneous disease. Affected patients show normocytic hemolytic anemia, jaundice and splenomegaly; gallstones are also frequently found. The clinical picture can vary greatly from an asymptomatic form to a severe life-threatening anemia that must be treated by blood transfusions and a splenectomy.

 

Inheritance can be autosomal dominant or recessive, with about two thirds of all cases showing dominant inheritance. In Northern Europe, pathogenic variants are found in the ANK1 gene, which codes for the protein ankyrin-1, in up to 65% of patients. Frameshift or stop mutations usually lead to a dominant phenotype and missense and promoter mutations to a recessive phenotype. The second most common cause is causative variants in the SLC4A1 gene, which lead to a defect in protein band 3. Heredity is autosomal dominant. Furthermore, about 15-30% of variants are described in ß-spectrin, which is encoded by the SPTB gene. In rare cases, α-spectrin or protein 4.2 are affected, each with a proportion of less than 5%.

 

The examination of the SPTA1, SPTB and EPB41 genes can also be carried out for suspected hereditary elliptocytosis or pyropoikilocytosis, as these are also caused by variants in these genes.

 

References

Eber und Andres AWMF Leitlinie Hereditäre Sphärozytose, 2016 / Zamora Schaefer Hereditary Spherocytosis. [Updated 2019 Mar 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan / Kalfa, Connor, Begtrup EPB42-Related Hereditary Spherocytosis. 2014 Mar 13 [Updated 2016 Nov 10]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.

GENES
ANK1, EPB42, SLC4A1, SPTA1, SPTB
ASSOCIATED TESTS
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