Congenital Dyserythropoietic Anemia Panel

Congenital dyserythropoietic anemia (CDA) is a disorder that results in defective erythropoiesis leading to anemia. There are four subgroups of CDAs: type I, type II, type III, and type IV. Type I accounts for ~12% of cases with onset in childhood. Symptoms include moderate to severe anemia, jaundice, hepatosplenomegaly, and in ~10% of cases, distal limb anomalies. Type II is the most common accounting for ~75% of CDA cases and over 300 cases worldwide. Onset occurs in adolescence or early adulthood with symptoms including mild to severe anemia, jaundice, hepatosplenomegaly, and gall stones. Type III patients present with mild anemia and jaundice, but splenomegaly is usually absent. Type IV CDA is a subgroup of disorders related to transcription factor mutations including two X-linked dominant forms due to pathogenic variants in GATA1 or ALAS2 (Iolascon et al. 2020. PubMed ID: 32702750; Iolascon et al. 2013. PubMed ID: 23940284).

Patients with CDA can be both transfusion dependent or independent. Chronic hemolytic anemia can result in iron overload leading to liver damage, heart failure, diabetes, and hypergonadotropic hypogonadism. Genetics is helpful in differential diagnosis of CDA types from other forms of hemolytic anemia and from acquired versus inherited forms of dyserythropoiesis. Genetic diagnosis is achieved in ~80% of cases of CDA (Iolascon et al. 2020. PubMed ID: 32702750).

Majeed syndrome is a multisystemic inflammatory condition with patients also presenting with CDA (Ferguson and El-Shanti. 2021. PubMed ID: 33670882). Additional clinical information can be found on the LPIN2 test page. 

CDA is inherited in an autosomal recessive manner through pathogenic variants in the CDAN1 (type I), CDIN1 (type I), and SEC23B (type II) genes. Missense pathogenic variants are predominant, and no patients homozygous for null pathogenic variants in either the CDAN1 or SEC23B genes have been documented. Consistent with this notion, Cdan1 knockout mice die in utero prior to erythropoiesis onset (Renella et al. 2011. PubMed ID: 21364188; Tao et al. 2012. PubMed ID: 22745161). Type III CDA is inherited in an autosomal dominant manner through pathogenic variation in the KIF23 gene with only one variant, c.2747C>G (p.Pro916Arg) being reported in a Swedish and an American family (Liljeholm et al. 2013. PubMed ID: 23570799). Type IV is due to KLF1 and GATA1 pathogenic variants associated with autosomal dominant and X-linked recessive forms of CDA type IV, respectively (Iolascon et al. 2020. PubMed ID: 32702750). Copy number variants are rare, with only one gross deletion being reported in the SEC23B and CDAN1 genes (Schwarz et al. 2009. PubMed ID: 19561605; Heimpel et al. 2006. PubMed ID: 16141353). De novo pathogenic variants are rarely reported in CDA cases (Iolascon et al. 2020. PubMed ID: 32702750). 

CDA has also been seen as a feature in some complex disorders including Majeed syndrome, developmental and epileptic encephalopathy, and macrocytic dyserythropoietic anemia. Majeed syndrome and developmental epileptic encephalopathy are inherited in an autosomal recessive manner due to pathogenic variants in the LPIN2 and CAD genes, respectively (Ferguson and El-Shanti. 2021. PubMed ID: 33670882; Russo et al. 2020. PubMed ID: 32720728). 

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

A genetic diagnosis is identified in ~80% of CDAs, with type II disease being most common. Pathogenic variants in SEC23B, CDAN1, CDIN1, GATA1, CAD and KLF1 account for 77.9%, 12.1%, 4%, 3.4%, 1.4%, and 1.4% of cases, respectively (Iolascon et al. 2020. PubMed ID: 32702750). Analytical sensitivity for the CDIN1, GATA1 and KLF1 genes should be high because all pathogenic variants reported to date are detectable by this method. 

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 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).