Clinical and genetic features of congenital dyserythropoietic anemia (CDA)

Abstract Introduction Congenital dyserythropoietic anemias ( CDA ) are characterized by hyporegenerative anemia with inadequate reticulocyte values, ineffective erythropoiesis, and hemolysis. Distinctive morphology of bone marrow erythroblasts and identification of causative genes allow classification into 4 types caused by variants in CDAN 1 , c15orf41 , SEC 23B , KIF 23 , and KLF 1 genes. Objective Identify pathogenic variants in CDA patients. Methods Massive parallel sequencing with a targeted gene panel, Sanger sequencing, Comparative Genome Hybridization ( CGH ), and in silico predictive analysis of pathogenicity. Results Pathogenic variants were found in 21 of 53 patients studied from 44 unrelated families. Six variants were found in CDAN 1: two reported, p.Arg714Trp and p.Arg725Trp and, four novel, p.Arg623Trp, p.Arg946Trp, p.Phe1125Ser and p.Ser1227Gly. Twelve variants were found in SEC 23B: seven reported, p.Arg14Trp, p.Glu109Lys, p.Arg217Ter, c.835‐2A>G, p.Arg535Ter, p.Arg550Ter and p.Arg718Ter and, five novel, p.Val164Leu, p.Arg190Gln, p.Gln521Ter, p.Arg546Trp, and p.Arg611Gln. The variant p.Glu325Lys in KLF 1 was found in one patient and p.Tyr365Cys in ALAS 2 in an other. Moreover, we identified genomic rearrangements by CGH in some SEC 23B‐monoallelic patients. Conclusions New technologies for genetic studies will help to find variants in other genes, in addition to those known, that contribute to or modulate the CDA phenotype or support the correct diagnosis.