Research Article: Two founder mutations in the SEC23B gene account for the relatively high frequency of CDA II in the Italian population

Date Published: September 14, 2011

Publisher: Wiley Subscription Services, Inc., A Wiley Company

Author(s): Roberta Russo, Antonella Gambale, Maria Rosaria Esposito, Maria Luisa Serra, Annaelena Troiano, Ilaria De Maggio, Mario Capasso, Lucio Luzzatto, Jean Delaunay, Hannah Tamary, Achille Iolascon.


Congenital Dyserythropoietic Anemia type II is an autosomal recessive disorder characterized by unique abnormalities in the differentiation of cells of the erythroid lineage. The vast majority of CDA II cases result from mutations in the SEC23B gene. To date, 53 different causative mutations have been reported in 86 unrelated cases (from the CDA II European Registry), 47 of them Italian. We have now identified SEC23B mutations in 23 additional patients, 17 Italians and 6 non-Italian Europeans. The relative allelic frequency of the mutations was then reassessed in a total of 64 Italian and 45 non-Italian unrelated patients. Two mutations, E109K and R14W, account for over one-half of the cases of CDA II in Italy. Whereas the relative frequency of E109K is similar in Italy and in the rest of Europe (and is also prevalent in Moroccan Jews), the relative frequency of R14W is significantly higher in Italy (26.3% vs. 10.7%). By haplotype analysis we demonstrated that both are founder mutations in the Italian population. By using the DMLE+ program our estimate for the age of the E109K mutation in Italian population is ≈2,200 years; whereas for the R14W mutation it is ≈3,000 years. We hypothesize that E109K may have originated in the Middle East and may have spread in the heyday of the Roman Empire. Instead, R14W may have originated in Southern Italy. The relatively high frequency of the R14W mutation may account for the known increased prevalence of CDA II in Italy. Am. J. Hematol. 86:727–732, 2011. © 2011 Wiley-Liss, Inc.

Partial Text

Congenital dyserythropoietic anemia (CDA) was first described in 1968 as a condition characterized by a paradoxical association of anemia and reticulocytopenia with erythroid hyperplasia in the bone marrow [1, 2]. It soon became clear that the condition was heterogeneous, and three forms became well known [1], with Type II being the most frequent. The prevalence of CDAs in Europe has been recently assessed. The combined prevalence of CDA I and CDA II (based on all cases reported in the last 42 years) has the highest value in Italy (2.49/million). CDA II (367 cases) is relatively more frequent than CDA I (122 cases), with an overall ratio of approximately 3.0 [3].

Subjects and relative allelic frequency assessment. To date, 86 unrelated european cases of CDA II due to 53 different causative mutations have been described [7–11]. Among them, 47 unrelated cases had Italian origin with 31 different mutations, 39 were non-Italian European (NIE) patients with 32 different mutations. Furthermore we included 17 Italian and 6 NIE unrelated cases still unpublished, with an overall count of 64 Italian and 45 NIE patients (Supporting Information Table Is).

CDA II results from mutations that cause loss of function of the SEC23B gene. As for other autosomal recessive conditions, it is not surprising that many different mutations are found in patients, because there are many amino acid changes that can produce loss of function. To date we know 53 different mutations in SEC23B causing CDA II [7–11]. Here, we expanded the cohort of CDA II patients of European Registry (109 CDA II cases) including 17 Italian and 6 NIE unrelated cases still unpublished.




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