New Cases and Mutations in SEC23B Gene Causing Congenital Dyserythropoietic Anemia Type II

Hereditary anemias; Ineffective erythropoiesis; Rare blood diseaseAnèmies hereditàries; Eritropoesi ineficaç; Malaltia rara de la sangAnemias hereditarias; Eritropoyesis ineficaz; Enfermedad rara de la sangreCongenital dyserythropoietic anemia type II (CDA II) is an inherited autosomal recessive blood disorder which belongs to the wide group of ineffective erythropoiesis conditions. It is characterized by mild to severe normocytic anemia, jaundice, and splenomegaly owing to the hemolytic component. This often leads to liver iron overload and gallstones. CDA II is caused by biallelic mutations in the SEC23B gene. In this study, we report 9 new CDA II cases and identify 16 pathogenic variants, 6 of which are novel. The newly reported variants in SEC23B include three missenses (p.Thr445Arg, p.Tyr579Cys, and p.Arg701His), one frameshift (p.Asp693GlyfsTer2), and two splicing variants (c.1512-2A>G, and the complex intronic variant c.1512-3delinsTT linked to c.1512-16_1512-7delACTCTGGAAT in the same allele). Computational analyses of the missense variants indicated a loss of key residue interactions within the beta sheet and the helical and gelsolin domains, respectively. Analysis of SEC23B protein levels done in patient-derived lymphoblastoid cell lines (LCLs) showed a significant decrease in SEC23B protein expression, in the absence of SEC23A compensation. Reduced SEC23B mRNA expression was only detected in two probands carrying nonsense and frameshift variants; the remaining patients showed either higher gene expression levels or no expression changes at all. The skipping of exons 13 and 14 in the newly reported complex variant c.1512-3delinsTT/c.1512-16_1512-7delACTCTGGAAT results in a shorter protein isoform, as assessed by RT-PCR followed by Sanger sequencing. In this work, we summarize a comprehensive spectrum of SEC23B variants, describe nine new CDA II cases accounting for six previously unreported variants, and discuss innovative therapeutic approaches for CDA II.This work was supported by NEOTEC grant SNEO-20191246 from Spanish CDTI to C.T., RETOS COLABORACION grant RTC2019-007074-1 from: MCIN/AEI/10.13039/501100011033 from Spanish Ministry of Science and Innovation (MICINN) to C.T. and M.S.; ARETHA grant PID2021-122436OB-I00 funded by MCIN/AEI/10.13039/501100011033 to M.S.; RTI-2018-101735-B-I100 from MCIN/AEI/10.13039/501100011033/ERDF “A way to make Europe” from the Spanish Ministry of Science and Innovation (MICINN) to M.S. M.M.M. is supported by a Marie Curie Fellowship from the European Commission under Horizon 2020 Framework Program Project: 894737. G.H. is supported by funds provided by the APU and ADISCON patient associations. L.R.-C. holds an FI-AGAUR predoctoral fellowship (2020FI-B00038) from Generalitat de Catalunya. X.F.-C. is partially supported by funds provided by the grant RTI-2018-101735-B-I100 from MCIN/AEI/10.13039/501100011033/ERDF “A way to make Europe”. V.V. was supported by funds provided by APU and ADISCON patient associations and UIC postdoctoral scholarship; she is currently supported by funds provided by RETOS COLABORACION grant RTC2019-007074-1 from MCIN/AEI/10.13039/501100011033 from Spanish Ministry of Science and Innovation (MICINN)

Newborn Screening for Sickle Cell Disease in Catalonia between 2015 and 2022-Epidemiology and Impact on Clinical Events

Hemoglobinopathies; Newborn screening; Sickle cell diseaseHemoglobinopatías; Cribado neonatal; DrepanocitosisHemoglobinopaties; Cribratge neonatal; DrepanocitosiAbstract In 2015, Catalonia introduced sickle cell disease (SCD) screening in its newborn screening (NBS) program along with standard-of-care treatments like penicillin, hydroxyurea, and anti-pneumococcal vaccination. Few studies have assessed the clinical impact of introducing NBS programs on SCD patients. We analyzed the incidence of SCD and related hemoglobinopathies in Catalonia and the change in clinical events occurring after introducing NBS. Screening 506,996 newborns from 2015 to 2022, we conducted a retrospective multicenter study including 100 screened (SG) and 95 unscreened (UG) SCD patients and analyzed SCD-related clinical events over the first six years of life. We diagnosed 160 cases of SCD, with an incidence of 1 in 3169 newborns. The SG had a significantly lower median age at diagnosis (0.1 y vs. 1.68 y, p < 0.0001), and initiated penicillin prophylaxis (0.12 y vs. 1.86 y, p < 0.0001) and hydroxyurea treatment earlier (1.42 y vs. 4.5 y, p < 0.0001). The SG experienced fewer median SCD-related clinical events (vaso-occlusive crisis, acute chest syndrome, infections of probable bacterial origin, acute anemia requiring transfusion, acute splenic sequestration, and pathological transcranial Doppler echography) per year of follow-up (0.19 vs. 0.77, p < 0.0001), a reduced number of annual emergency department visits (0.37 vs. 0.76, p < 0.0001), and fewer hospitalizations (0.33 vs. 0.72, p < 0.0001). SCD screening in Catalonia’s NBS program has effectively reduced morbidity and improved affected children’s quality of life.L'any 2015, Catalunya va introduir el cribratge de la malaltia de cèl·lules falciformes (SCD) al seu programa de cribratge de nounats (NBS) juntament amb tractaments d'atenció estàndard com la penicil·lina, la hidroxiurea i la vacunació antipneumocòcica. Pocs estudis han avaluat l'impacte clínic de la introducció de programes NBS en pacients amb MSC. S'ha analitzat la incidència de la MSC i les hemoglobinopaties relacionades a Catalunya i el canvi en els esdeveniments clínics que es produeixen després de la introducció de l'ENB. Vam examinar 506.996 nadons del 2015 al 2022, vam realitzar un estudi multicèntric retrospectiu que incloïa 100 pacients amb SCD examinats (SG) i 95 sense cribratge (UG) i vam analitzar els esdeveniments clínics relacionats amb SCD durant els primers sis anys de vida. Es van diagnosticar 160 casos de MSC, amb una incidència d'1 de cada 3.169 nounats. El SG tenia una edat mitjana significativament més baixa en el moment del diagnòstic (0,1 anys vs. 1,68 anys, p <0,0001) i va iniciar la profilaxi amb penicil·lina (0,12 anys vs. 1,86 anys, p <0,0001) i el tractament amb hidroxiurea abans (1,42 anys vs. 4,5 anys). , p <0,0001). El SG va experimentar menys esdeveniments clínics mitjans relacionats amb SCD (crisi vaso-oclusiva, síndrome toràcica aguda, infeccions d'origen bacterià probable, anèmia aguda que va requerir transfusió, segrest esplènic agut i ecografia Doppler transcranial patològica) per any de seguiment (0,19 vs. 0,77, p <0,0001), un nombre reduït de visites anuals al servei d'urgències (0,37 vs. 0,76, p <0,0001) i menys hospitalitzacions (0,33 vs. 0,72, p <0,0001). El cribratge de SCD al programa NBS de Catalunya ha reduït de manera efectiva la morbiditat i ha millorat la qualitat de vida dels nens afectats