Analysis of a cohort of 101 CDAII patients: description of 24 new molecular variants and genotype‐phenotype correlations

Abstract

Congenital dyserythropoietic anaemia type II (CDAII) is a rare autosomal recessive disease characterized by ineffective erythropoiesis, haemolysis, erythroblast morphological abnormalities, hypoglycosylation of some red blood cell membrane proteins, particularly band 3, and mutations in the SEC23B gene. We report the analysis of 101 patients from 91 families with a median follow-up of 23 years (range 0-65); 68 patients are newly reported. Clinical and haematological parameters were separately analysed in early infancy and thereafter, when feasible. Molecular analysis of the SEC23B gene confirmed the high heterogeneity of the defect, leading to the identification of 54 different mutations, 24 of which are newly described. To evaluate the genotype-phenotype correlation, patients were grouped according to their genotype (two missense mutations vs. one missense/one drastic mutation) and assigned to two different severity gradings based on laboratory data and on therapeutic needs; by this approach only a weak genotype-phenotype correlation was observed in the analysed groups.

Clinical and genetic features of congenital dyserythropoietic anemia (CDA)

“…31,34 The variability in the phenotypic expression of CDA among patients or family members with the same genetic variant was observed in cohort studies, indicating the possibility of other genes or epigenetic factors modulating the expression of the disease. 28 In this sense, a mechanism of compensation mediated by the isoform of SEC23A in the core trafficking machinery COPII coat complex was demonstrated. 65,66 Moreover, biallelic variants in the PARP4 gene were reported in CDA patients with no pathogenic variants in the SEC23B gene whose whole exome was analyzed.…”

“…ant in the GATA1 nor ALAS2 genes, neither the big deletion comprising exons 3 and 4 of the SEC23B gene as reported by other authors in CDA type II patients. 14,28 In those patients, the genetic study by CGH, at the resolution established in the array, ruled out rearrangements affecting the genes CDAN1, c15orf41, SEC23B, KIF23, and GATA1, but not in the KLF1 gene because it was not covered in the array. The bone marrow responsiveness index (BMRI) was proposed as a diagnostic tool to discriminate between patients with CDA from those with hemolytic anemias such as hereditary spherocytosis, with the cutoff value of BMRI <121.…”

CD44 as a Potential Screening Marker for Preliminary Differentiation Between Congenital Dyserythropoietic Anemia Type II and Hereditary Spherocytosis

“…The average incidence in Europe is about one family per million (1) but it can be higher in some countries or communities particularly with founder mutations, e.g., Southern Italy (2), Moroccan Jews (3), and Indian Agrawals (4). When determined in serial analyses, absolute reticulocyte counts can show a discrimination between CDAII and other hemolytic anemias with similar clinical course (6). Blood smears show definite but nonspecific abnormalities, such as, anisopoikilocytosis, basophilic stippling of red blood cells (RBCs), suboptimal polychromasia, and variable degrees of spherocytosis.…”

“…5). When determined in serial analyses, absolute reticulocyte counts can show a discrimination between CDAII and other hemolytic anemias with similar clinical course (6). Light microscopy of bone marrow shows dyserythropoiesis and multinuclearity with 10-40% bi-nucleated or some multinucleated late erythroblasts.…”

GATA1 erythroid-specific regulation of SEC23B expression and its implication in the pathogenesis of congenital dyserythropoietic anemia type II

“…[1][2][3] However, several cases show an incomplete inheritance pattern or no mutations within the gene. Mutations in cis-acting regulatory elements of SEC23B as well as digenic inheritance was hypothesized as additional genetic etiology of CDAII.…”