Hereditary Xerocytosis via the PIEZO1 Gene

Hereditary Xerocytosis (HX), also called dehydrated hereditary stomatocytosis, is a mild to moderate form of hemolytic anemia characterized by dehydrated red blood cells. The dehydrated red blood cell phenotype is due to defects in cation permeability rendering cells susceptible to lysis via shear stress (Platt et al. 1981). HX primarily presents in adults with mild anemia and symptoms including fatigue, macrocytosis, reticulocytosis, splenomegaly, jaundice, and cholelithiasis (Albuisson et al. 2013). Genetic testing is helpful in the differential diagnosis of HX from other forms of hemolytic anemia including hereditary spherocytosis, hemoglobinopathies, and enzyme deficiency anemias including pyruvate kinase deficiency. Early diagnosis is often helpful in monitoring of cholelithiasis and prevention of iron overload through regular monitoring of serum ferritinemia (An and Mohandas 2008).

In autosomal recessive forms of the disease, severe lymphatic dysplasia with non-immune hydrops fetalis has been reported in perinatal patients with widespread lymphedema, pleural effusions, chylothoraces, and/or pericardial effusions. This form of the disease is phenotypically similar to other generalized lymphatic dysplasia disorders including Hennekam Lymphagiectasia-Lymphedema syndrome (Fotiou et al. 2015). Pseudohyperkalemia has also been reported in patients with HX. Due to the defect in cation permeability, blood samples stored at room temperature result in hyperkalemia lab results (Iolascon et al. 1999; Grootenboer et al. 1998).

HX is inherited in an autosomal dominant manner through pathogenic variants in the PIEZO1 and KCNN4 genes. PIEZO is a mechanically activated cation channel that facilitates potassium and sodium transport. Gain of function missense variants in the PIEZO1 gene lead to increased permeability of cations resulting in HX (Albuisson et al. 2013; Andolfo et al. 2013). Missense variants are primarily located between exons 16-24 and 42-51. An in-frame deletion has also been reported in PIEZO1 gene for HX patients (Andolfo et al. 2013). In patients with HX, decreased osmotic fragility is present in individuals with pathogenic variants, however, clinical presentation is variable (Andolfo et al. 2013; Albuisson et al. 2013). Lymphatic dysplasia with non-immune hydrops fetalis via the PIEZO1 gene is inherited in an autosomal recessive manner. Missense, nonsense, and splice site alterations resulting in loss of PIEZO function have been reported (Lukacs et al. 2015; Fotiou et al 2015). Similar hematologic phenotypes are seen in morpholino knockdown of piezo1 in zebrafish (Faucherre et al. 2014).

Clinical sensitivity for the PIEZO1 gene is currently unknown due to the limited number of cases reported to date. In HX kindreds with pathogenic variants in the PIEZO1 gene, individuals with the familial variant presented with decreased osmotic fragility indicative of disease (Albuisson et al. 2013). Analytical sensitivity for the PIEZO1 gene should be high as all pathogenic variants to date are detectable by sequencing.

This test provides full coverage of all coding exons of the PIEZO1 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).