Hereditary Spherocytosis Type 1 via the ANK1 Gene

Hereditary Spherocytosis (HS) is a condition where red blood cells lose their typical biconcave disc shape and appear spherical. It is characterized by anemia due to chronic extravascular hemolysis, jaundice, formation of bilirubin gallstones, reticulocytosis and splenomegaly (Aster et al. 2013). Disease symptoms can vary greatly with modest forms of the disease being most common (60-75% of cases). Mild forms of HS may be asymptomatic until adulthood, while more severe forms occur postnatally with life threatening anemia. There are five sub-types of HS with type I representing about half of HS cases defined by mutations in the ANK1 gene. Therapeutic intervention for severe cases includes partial splenectomy and/or regular transfusions to decrease hemolysis, increase hemoglobin levels, and limit development of bilirubin gallstones (Seims et al. 2013).

Type 1 HS is inherited in an autosomal dominant and recessive manners due to mutations in the ANK1 gene. Disease severity ranges from mild to severe and is dependent on the extent of membrane defect. De novo mutations are found in approximately 30% of cases (Miraglia del Gudice et al. 2001). HS occurs in 1 in 2,000 individuals of Northern European ancestry and is less common in other ethnic backgrounds. Type I HS is solely defined by mutations throughout the ANK1 gene with the majority of mutations leading to premature termination (Gallagher and Forget 1998; Ozcan et al. 2003; Nakanishi et al. 2001). Substitution mutations at c. -153 and c.-108 within the upstream promoter region are also causative for disease (Gallagher et al. 2010). Mutations in SPTA1, SPTB, SLC4A1 and EPB42 also have been reported to cause HS and are responsible for ~40% of HS cases. The ANK1 gene encodes the protein ANKYRIN1 which tethers integral membrane proteins to the underlying spectrin-actin cytoskeleton allowing red blood cells to adopt a biconcave disc shape. The biconcave disc morphology is essential for providing flexibility to red blood cells enabling them to transverse narrow splenic capillaries.

Sequencing is capable of detecting >95% of mutations within the ANK1 gene. Mutations in the ANK1 gene are responsible for about half of HS cases (Aster et al. 2013).

This test provides full coverage of all coding exons of the ANK1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).