Congenital Dyserythropoietic Anemia Type I via the CDIN1/C15orf41 Gene

Congenital Dyserythropoietic Anemia (CDA) is a disorder that affects erythropoiesis leading to anemia. There are four types of CDA caused by mutations 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. Genetics 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. 2012; Tamary and Dgany 2009). Type I CDA is the second most prevalent form of disease and is characterized by moderate to severe anemia through mutations in either the CDAN1 or CDIN1/C15ORF41 genes. Patients with Type I CDA via CDIN1 gene mutations had severe anemia requiring blood transfusions during early childhood. Other clinical features included megaloblastic erythrocytosis with bi and multi-nuclear erythroblasts (Babbs et al. 2013; Iolascon et al. 2012).

Type I CDA is primarily inherited in an autosomal recessive manner through mutations in the CDAN1 gene. Recently, Babbs et al. (2013) identified recessive causative mutations in a second gene, CDIN1. Two missense mutations have been reported with the c.533T>A (p.Leu178Gln) and the c.281A>G (p.Try94Cys) variants being reported in one Middle-Eastern family and two East Asian families respectively (Babbs et al. 2013). While the exact function of the CDIN1 protein is unknown, it is a member of the Holliday junction resolvase family and thought to be involved in DNA repair (Babbs et al. 2013).

Analytical sensitivity for the CDIN1 gene should be high because all mutations reported to date are detectable by this method. Clinical sensitivity for CDIN1 is unknown due to the small number of patients reported to date.

This test provides full coverage of all coding exons of the CDIN1 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).