Molecular diagnostics for Hereditary Anemia

Anemia may be classified as impaired red blood cell (RBC) production or increased RBC destruction (hemolytic anemias). Hereditary anemia may be clinically highly variable, including mild, moderate, or severe forms. Underlying cause of hereditary anemia may be due to

Hemoglobinopathies 

Thalassemias represent a major group of inherited disorders of hemoglobin synthesis. Together with structural hemoglobin variants these hemoglobinopathies are among the most common genetic disorders worldwide, occurring more frequently in people originating from (former) malaria regions, the Mediterranean, the Indian subcontinent, Southeast Asia and Africa.

Red blood cell membrane defects

Hereditary spherocytosis and hereditary elliptocytosis are other examples of inherited hemolytic anemias. Hereditary spherocytosis is the most common congenital hemolytic anemia among Caucasians with an estimated prevalence ranging from 1:2,000 to 1:4,000. Elliptocytosis/ovalocytosis has about the same prevalence but is often clinically silent, however sever forms are described e.g. pyropoikilocytosis. Stomatocytosis/xerocytosis is a rare disease and like the membrane defects presented with a specific red cell shape.

Enzyme deficiencies

Glucose-6-phosphate dehydrogenase (G6PD) is the most common cause of acute hemolytic anemia in people originating from the Mediterranean, Africa and Asia. Pyruvate kinase (PK) deficiency is a common defect in red blood cell glycolysis and responsible for chronic hemolytic anemia. Other red blood cell enzyme deficiencies are rare and may effect energy supply like in PK deficiency or diminish protection against reactive oxygen species like in G6PD deficiency.

Bone marrow failure

Inherited bone marrow failure syndromes are genetic disorders characterized by the inability of the bone marrow to produce sufficient blood cells. Bone marrow failure can affect all blood cell lineages with clinical symptoms similar to aplastic anemia, or be restricted to a limited number of blood cell lineages e.g presented with thrombocytopenia or neutropenia. Bone marrow failure may be accompanied by physical abnormalities like a short stature and skin pigmentation in Fanconi anemia and dystrophic nails, lacy reticular pigmentation and oral leukoplakia in dyskeratosis congenita. Patients with inherited bone marrow failure syndrome have an increased risk of developing cancer—either hematological or solid tumors. Early diagnosis is important for management and surveillance of the diseases. Accurate genetic diagnosis is important to confirm the clinical diagnosis of phenotypes like Fanconi anemia, Diamond-Blackfan anemia, dyskeratosis congenita, Shwachman-Diamond syndrome and WAS-related disorders.

To investigate hereditary causes of anemia four targeted NGS panels are constructed. Choose the links above for more information.