Morphological and molecular features of patients with CDA. (A) Light microscopy analysis of the bone marrow from patients with different CDA subtypes. CDA patients generally show erythroid hyperplasia. Red arrows indicate typical findings for each CDA subtype: CDAI, internuclear chromatin bridging; CDAII, binucleate erythroid precursors; CDAIII, giant multinucleated erythroblasts; CDAIV, multinucleate erythroblasts; and CAD deficiency, binucleate CDAII-like precursors. (B) Pie chart showing the frequencies of the different CDA subtypes diagnosed after genetic testing in patients clinically suspected of having CDA. The frequency of each condition was calculated as the ratio between the number of patients in each CDA subtype and the overall count of patients tested (n = 218 patients [those included in our international registry of CDAs from 1995 to 2019]). Six patients originally suspected of CDA showed conclusive diagnosis of acquired dyserythropoiesis: 2 patients with liver failure, 2 with iron-deficiency anemia, 1 with erythrophagocytosis, and 1 with transient erythroblastopenia. Syndromic CDA refers to 1 patient with a mutation in the CAD gene. GATA1-related cytopenias include: X-linked thrombocytopenia with or without dyserythropoietic anemia; congenital erythropoietic porphyria; and idiopathic cytopenias of undetermined significance. Other hereditary anemias (HA) include: hereditary spherocytosis; hereditary dehydrated stomatocytosis; red cell enzymatic defects; and sideroblastic anemia. The undiagnosed cases were evaluated by analysis of the CDA gene panel, by extended targeted next-generation sequencing for hereditary anemias, or by whole-exome sequencing. (C) Bubble chart defining the lengths of the coding sequences of each CDA-causative gene and their relative pathogenicity scores. These scores were calculated by combining the constraint metrics of each gene available at the ExAC database (http://exac.broadinstitute.org/). High pathogenicity scores identify increased constraints (intolerance to variation). The more intolerant to variation a gene is, the less likely it is to be mutated. The size of each bubble represents the frequency of the mutations in each gene, as calculated by the ratio of the number of mutated alleles for each gene and the overall count of disease alleles (n = 149, from 78 patients included in our international registry of CDAs from 2008 to 2019).