Clinical Information

Next-generation sequencing (NGS) is a methodology that can interrogate large regions of genomic DNA in a single assay. The presence and pattern of gene mutations can provide critical diagnostic, prognostic, and therapeutic information for managing physicians.

This test is best interpreted in the context of protein studies and peripheral blood findings. This can be provided by also ordering the RBCME / Red Blood Cell Membrane Evaluation test. Please fill out the information sheet and indicate that NGS testing was ordered. Providing CBC data and clinical notes will also allow more precise interpretation of results.

This panel aids in the diagnosis and genetic counseling of individuals with RBC membrane disorders including hereditary spherocytosis, hereditary elliptocytosis, hereditary pyropoikilocytosis, Southeast Asian ovalocytosis, hereditary stomatocytosis (both overhydrated and dehydrated/hereditary xerocytosis subtypes), and cryohydrocytosis(1-3).

The functional red cell membrane is composed of a cholesterol and phospholipid bilayer anchored by integral proteins to an elastic cytoskeletal network. These interactions form the shape, deformability, and proper ion balance of the cell. Abnormalities in these moieties result in red blood cell membrane disorders. Hereditary spherocytosis (HS) is a common membrane disorder that can be present in all ethnic groups. It is usually associated with visible spherocytes on the peripheral blood smear and can be associated with variable clinical features of hemolysis ranging from mild to severe. Paradoxically, erythrocytosis can occur after splenectomy. Hereditary elliptocytosis (HE) is another fairly common and clinically variable disorder that can range from normal RBC indices in the large majority of cases to a minor subset of patients with moderate to severe anemia. Common hereditary elliptocytosis (CHE) is characterized by the presence of elliptocytes on the peripheral blood smear and the absence of anemia. Mutations associated with HE have been reported in widely variable ethnicities with greater prevalence in populations overlapping the malaria belt. Hereditary pyropoikilocytosis (HPP) is now best classified as a severe form of hereditary elliptocytosis. It is uncommon and presents in early childhood as a severe hemolytic anemia. These disorders are associated with marked poikilocytosis on the peripheral blood smear.(1,2) Hereditary stomatocytosis is an RBC membrane permeability disorder that can manifest as the more common dehydrated hereditary stomatocytosis (DHSt), also known as hereditary xerocytosis (HX), and the rarer overhydrated hereditary stomatocytosis (OHSt) subtypes.These disorders are important to confirm or exclude as splenectomy has been associated with an increased risk for serious venous thrombosis and thromboembolism events and is contraindicated in published guidelines.(4) DHSt/HX manifests variably as mild to compensated anemia to some cases with increased hemoglobin levels. Some patients are asymptomatic, others show hemolysis after even nontraumatic exercise sessions. Others display perinatal edema and susceptibility to iron overload. DHSt/HX is associated with pseudohyperkalemia, increased MCHC, and decreased osmotic fragility due to relative dehydration of the red blood cell. OHSt is similarly is associated with anemia of variably severity, but is associated with increased osmotic fragility due to a relatively overhydrated steady state.