Congenital Dyserythropoietic Anemia Type IV via the KLF1 Gene

Congenital Dyserythropoietic Anemia (CDA) is a disorder that affects erythropoiesis leading to anemia. There are four types of CDA caused by pathogenic variants in different genes. Overlapping symptoms include jaundice and splenomegaly. Chronic anemia can cause secondary hemochromatosis and lead to tissue damage and organ failure in severe cases. Genetic testing is helpful in differential diagnosis of CDA types and from other broader syndromes where CDA also occurs including Majeed Syndrome, Mevalonate Kinase Deficiency, and exocrine pancreatic insufficiency (Iolascon et al. 2013; Tamary and Dgany 2009).

Type IV CDA is the third most common form with about 70 cases reported to date. The majority of these cases as part of a broader spectrum disorder such as Majeed syndrome, and mevalonate kinase deficiency. Type IV clinical presentation is heterogeneous and likely represents multiple unrelated disorders. However, due to relatively few patients, additional subclasses for type IV CDA have not been described (Iolascon et al. 2013).

Type IV CDA is inherited in an autosomal dominant manner through pathogenic variants in the KLF1 gene. In 2010, the KLF1 gene was first documented to be involved in CDA. The c.937G>A (p.Glu325Lys) variant has been reported most frequently for type IV CDA. The KLF1 gene encodes an erythrocyte specific transcription factor, Krupple-like factor 1. The c.937G>A variant results in a dominant negative effect leading to impairment of KLF1 transcription activity and loss of Aquaporin 1 and CD44 expression (Araud et al. 2010). Severe transfusion dependent anemia has been reported in neonates with two pathogenic variants in the KLF1 gene (Viprakasit et al. 2014; Magor et al. 2015). Pathogenic variants in the KLF1 gene have also been associated with changes in hemoglobin levels, mainly increased expression of fetal hemoglobin (Gallienne et al. 2012).

Clinical sensitivity is unknown due to the small number of patients being reported to date. Analytical sensitivity for the KLF1 gene should be high because all pathogenic variants reported to date are detectable by sequencing.

This test provides full coverage of all coding exons of the KLF1 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).