Diagnostic Criteria
Suggestive Findings Congenital dyserythropoietic anemia type I (CDA I) should be suspected in individuals with the following laboratory and clinical findings. Laboratory features • Moderate-to-severe macrocytic anemia with mean corpuscular volume (MCV) 90 fL in the presence of normal folic acid and serum vitamin B12 levels • Inappropriately low number of reticulocytes for the degree of anemia compared to other hemolytic anemias (secondary to ineffective erythropoiesis) • On peripheral blood smear: macrocytosis, elliptocytes, basophilic stippling, and occasional mature nucleated erythrocytes • In bone marrow aspirate: • On light microscopy, erythroid hyperplasia, few double-nucleated erythroblasts, and interchromatin bridges between erythroblasts (in 0.6%-2.8% of erythroblasts) • On electron microscopy, erythroid precursors with spongy appearance of heterochromatin (in ≤60% of erythroblasts) and invaginations of the nuclear membrane Clinical features • Jaundice • Splenomegaly resulting from marrow expansion secondary to ineffective erythropoiesis • Distal limb anomalies including hypoplastic nails and syndactyly Establishing the Diagnosis The diagnosis of CDA I is established in a proband with and biallelic pathogenic variants in CDAN1 or CDIN1 identified on molecular genetic testing. Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in are likely to be diagnosed using gene-targeted testing , whereas those with a phenotype indistinguishable from many other inherited disorders with anemia are more likely to be diagnosed using genomic testing . Option 1 Single-gene testing. Targeted analysis for the pathogenic variant in CDAN1 can be performed first in individuals of Bedouin ancestry. A multigene panel that includes CDAN1, CDIN1, and other genes of interest is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. Option 2 Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. Table 1. Molecular Genetic Testing Used in Congenital Dyserythropoietic Anemia Type I (CDA I)
