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1. Second allogeneic stem cell transplantation can rescue a significant proportion of patients with JMML relapsing after first allograft

Author

Vinci, L., Flotho, C., Noellke, P., Lebrecht, D., Masetti, R., de Haas, V., De Moerloose, B., Dworzak, M., Hasle, H., Gungor, T., Stary, J., Turkiewicz, D., Ussowicz, M., de Heredia, C. D., Buechner, J., Jahnukainen, K., Kallay, K., Bodova, I., Smith, O. P., Zecca, M., Bresters, D., Lang, P., Masmas, T. N., Meisel, R., Pichler, H., Erlacher, M., Gohring, G., Locatelli, Franco, Strahm, B., Niemeyer, C. M., Yoshimi, A., Locatelli F. (ORCID:0000-0002-7976-3654), Vinci, L., Flotho, C., Noellke, P., Lebrecht, D., Masetti, R., de Haas, V., De Moerloose, B., Dworzak, M., Hasle, H., Gungor, T., Stary, J., Turkiewicz, D., Ussowicz, M., de Heredia, C. D., Buechner, J., Jahnukainen, K., Kallay, K., Bodova, I., Smith, O. P., Zecca, M., Bresters, D., Lang, P., Masmas, T. N., Meisel, R., Pichler, H., Erlacher, M., Gohring, G., Locatelli, Franco, Strahm, B., Niemeyer, C. M., Yoshimi, A., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

NO ABSTRACT

Published
2023

2. Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes

Author

Sahoo S. S., Pastor V. B., Goodings C., Voss R. K., Kozyra E. J., Szvetnik A., Noellke P., Dworzak M., Stary J., Locatelli F., Masetti R., Schmugge M., De Moerloose B., Catala A., Kallay K., Turkiewicz D., Hasle H., Buechner J., Jahnukainen K., Ussowicz M., Polychronopoulou S., Smith O. P., Fabri O., Barzilai S., de Haas V., Baumann I., Schwarz-Furlan S., Moerloose B. D., Smith O., Haas V. D., Gohring G., Niemeyer C., Nebral K., Simonitsch-Kluppp I., Paepe P. D., Van Roy N., Campr V., Zemanova Z., Clasen-Linde E., Plesner T., Schlegelberger B., Rudelius M., Manola K., Stefanaki K., Csomor J., Andrikovics H., Betts D., O'Sullivan M., Zohar Y., Jeison M., Vito R. D., Pasquali F., Maldyk J., Haus O., Alaiz H., Kjollerstrom P., Lemos L. M., Bodova I., Cermak M., Plank L., Gazic B., Kavcic M., Podgornik H., Ros M. L., Cervera J., Gengler C., Tchinda J., Beverloo B., Leguit R., Niewisch M. R., Sauer M. G., Burkhardt B., Lang P., Bader P., Beier R., Muller I., Albert M. H., Meisel R., Schulz A., Cario G., Panda P. K., Wehrle J., Hirabayashi S., Derecka M., Durruthy-Durruthy R., Yoshimi-Noellke A., Ku M., Lebrecht D., Erlacher M., Flotho C., Strahm B., Niemeyer C. M., Wlodarski M. W., Sahoo S.S., Pastor V.B., Goodings C., Voss R.K., Kozyra E.J., Szvetnik A., Noellke P., Dworzak M., Stary J., Locatelli F., Masetti R., Schmugge M., De Moerloose B., Catala A., Kallay K., Turkiewicz D., Hasle H., Buechner J., Jahnukainen K., Ussowicz M., Polychronopoulou S., Smith O.P., Fabri O., Barzilai S., de Haas V., Baumann I., Schwarz-Furlan S., Moerloose B.D., Smith O., Haas V.D., Gohring G., Niemeyer C., Nebral K., Simonitsch-Kluppp I., Paepe P.D., Van Roy N., Campr V., Zemanova Z., Clasen-Linde E., Plesner T., Schlegelberger B., Rudelius M., Manola K., Stefanaki K., Csomor J., Andrikovics H., Betts D., O'Sullivan M., Zohar Y., Jeison M., Vito R.D., Pasquali F., Maldyk J., Haus O., Alaiz H., Kjollerstrom P., Lemos L.M., Bodova I., Cermak M., Plank L., Gazic B., Kavcic M., Podgornik H., Ros M.L., Cervera J., Gengler C., Tchinda J., Beverloo B., Leguit R., Niewisch M.R., Sauer M.G., Burkhardt B., Lang P., Bader P., Beier R., Muller I., Albert M.H., Meisel R., Schulz A., Cario G., Panda P.K., Wehrle J., Hirabayashi S., Derecka M., Durruthy-Durruthy R., Yoshimi-Noellke A., Ku M., Lebrecht D., Erlacher M., Flotho C., Strahm B., Niemeyer C.M., Wlodarski M.W., and Clinical Genetics

Subjects
Oncology, Male, medicine.medical_specialty, Monosomy, Adolescent, Somatic cell, Medizin, Bone Marrow Cells, Kaplan-Meier Estimate, General Biochemistry, Genetics and Molecular Biology, Germline, Article, Clonal Evolution, Germline mutation, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, Child, Germ-Line Mutation, Chromosome 7 (human), Cytopenia, clonal hemopoiesis, business.industry, Myelodysplastic syndromes, Tumor Suppressor Proteins, Intracellular Signaling Peptides and Proteins, High-Throughput Nucleotide Sequencing, Infant, General Medicine, medicine.disease, GATA2 Transcription Factor, SAMD9 and SAMD9L mutations, Pediatric Myelodysplastic syndromes, medicine.anatomical_structure, HEK293 Cells, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Child, Preschool, Myelodysplastic Syndromes, Female, Bone marrow, Clonal Hematopoiesis, Single-Cell Analysis, business
Abstract

Germline SAMD9 and SAMD9L mutations (SAMD9/9Lmut) predispose to myelodysplastic syndromes (MDS) with propensity for somatic rescue. In this study, we investigated a clinically annotated pediatric MDS cohort (n = 669) to define the prevalence, genetic landscape, phenotype, therapy outcome and clonal architecture of SAMD9/9L syndromes. In consecutively diagnosed MDS, germline SAMD9/9Lmut accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the cohort. Among SAMD9/9Lmut cases, refractory cytopenia was the most prevalent MDS subtype (90%); acquired monosomy 7 was present in 38%; constitutional abnormalities were noted in 57%; and immune dysfunction was present in 28%. The clinical outcome was independent of germline mutations. In total, 67 patients had 58 distinct germline SAMD9/9Lmut clustering to protein middle regions. Despite inconclusive in silico prediction, 94% of SAMD9/9Lmut suppressed HEK293 cell growth, and mutations expressed in CD34+ cells induced overt cell death. Furthermore, we found that 61% of SAMD9/9Lmut patients underwent somatic genetic rescue (SGR) resulting in clonal hematopoiesis, of which 95% was maladaptive (monosomy 7 ± cancer mutations), and 51% had adaptive nature (revertant UPD7q, somatic SAMD9/9Lmut). Finally, bone marrow single-cell DNA sequencing revealed multiple competing SGR events in individual patients. Our findings demonstrate that SGR is common in SAMD9/9Lmut MDS and exemplify the exceptional plasticity of hematopoiesis in children. This analysis of a large, clinically annotated cohort of individuals with predisposition to myelodysplastic syndromes reveals insights into the genetic determinants of disease progression and their relationship with clinical manifestations and therapy outcome.

Published
2021
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3. Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes

Author

Sahoo, S. S., Pastor, V. B., Goodings, C., Voss, R. K., Kozyra, E. J., Szvetnik, A., Noellke, P., Dworzak, M., Stary, J., Locatelli, Franco, Masetti, R., Schmugge, M., De Moerloose, B., Catala, A., Kallay, K., Turkiewicz, D., Hasle, H., Buechner, J., Jahnukainen, K., Ussowicz, M., Polychronopoulou, S., Smith, O. P., Fabri, O., Barzilai, S., de Haas, V., Baumann, I., Schwarz-Furlan, S., Smith, O., Haas, V. D., Gohring, G., Niemeyer, C., Nebral, K., Simonitsch-Kluppp, I., Paepe, P. D., Van Roy, N., Campr, V., Zemanova, Z., Clasen-Linde, E., Plesner, T., Schlegelberger, B., Rudelius, M., Manola, K., Stefanaki, K., Csomor, J., Andrikovics, H., Betts, D., O'Sullivan, M., Zohar, Y., Jeison, M., Vito, R. D., Pasquali, F., Maldyk, J., Haus, O., Alaiz, H., Kjollerstrom, P., Lemos, L. M., Bodova, I., Cermak, M., Plank, L., Gazic, B., Kavcic, M., Podgornik, H., Ros, M. L., Cervera, J., Gengler, C., Tchinda, J., Beverloo, B., Leguit, R., Niewisch, M. R., Sauer, M. G., Burkhardt, B., Lang, P., Bader, P., Beier, R., Muller, I., Albert, M. H., Meisel, R., Schulz, A., Cario, G., Panda, P. K., Wehrle, J., Hirabayashi, S., Derecka, M., Durruthy-Durruthy, R., Yoshimi-Noellke, A., Ku, M., Lebrecht, D., Erlacher, M., Flotho, C., Strahm, B., Niemeyer, C. M., Wlodarski, M. W., Locatelli F. (ORCID:0000-0002-7976-3654), Sahoo, S. S., Pastor, V. B., Goodings, C., Voss, R. K., Kozyra, E. J., Szvetnik, A., Noellke, P., Dworzak, M., Stary, J., Locatelli, Franco, Masetti, R., Schmugge, M., De Moerloose, B., Catala, A., Kallay, K., Turkiewicz, D., Hasle, H., Buechner, J., Jahnukainen, K., Ussowicz, M., Polychronopoulou, S., Smith, O. P., Fabri, O., Barzilai, S., de Haas, V., Baumann, I., Schwarz-Furlan, S., Smith, O., Haas, V. D., Gohring, G., Niemeyer, C., Nebral, K., Simonitsch-Kluppp, I., Paepe, P. D., Van Roy, N., Campr, V., Zemanova, Z., Clasen-Linde, E., Plesner, T., Schlegelberger, B., Rudelius, M., Manola, K., Stefanaki, K., Csomor, J., Andrikovics, H., Betts, D., O'Sullivan, M., Zohar, Y., Jeison, M., Vito, R. D., Pasquali, F., Maldyk, J., Haus, O., Alaiz, H., Kjollerstrom, P., Lemos, L. M., Bodova, I., Cermak, M., Plank, L., Gazic, B., Kavcic, M., Podgornik, H., Ros, M. L., Cervera, J., Gengler, C., Tchinda, J., Beverloo, B., Leguit, R., Niewisch, M. R., Sauer, M. G., Burkhardt, B., Lang, P., Bader, P., Beier, R., Muller, I., Albert, M. H., Meisel, R., Schulz, A., Cario, G., Panda, P. K., Wehrle, J., Hirabayashi, S., Derecka, M., Durruthy-Durruthy, R., Yoshimi-Noellke, A., Ku, M., Lebrecht, D., Erlacher, M., Flotho, C., Strahm, B., Niemeyer, C. M., Wlodarski, M. W., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Germline SAMD9 and SAMD9L mutations (SAMD9/9Lmut) predispose to myelodysplastic syndromes (MDS) with propensity for somatic rescue. In this study, we investigated a clinically annotated pediatric MDS cohort (n = 669) to define the prevalence, genetic landscape, phenotype, therapy outcome and clonal architecture of SAMD9/9L syndromes. In consecutively diagnosed MDS, germline SAMD9/9Lmut accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the cohort. Among SAMD9/9Lmut cases, refractory cytopenia was the most prevalent MDS subtype (90%); acquired monosomy 7 was present in 38%; constitutional abnormalities were noted in 57%; and immune dysfunction was present in 28%. The clinical outcome was independent of germline mutations. In total, 67 patients had 58 distinct germline SAMD9/9Lmut clustering to protein middle regions. Despite inconclusive in silico prediction, 94% of SAMD9/9Lmut suppressed HEK293 cell growth, and mutations expressed in CD34+ cells induced overt cell death. Furthermore, we found that 61% of SAMD9/9Lmut patients underwent somatic genetic rescue (SGR) resulting in clonal hematopoiesis, of which 95% was maladaptive (monosomy 7 ± cancer mutations), and 51% had adaptive nature (revertant UPD7q, somatic SAMD9/9Lmut). Finally, bone marrow single-cell DNA sequencing revealed multiple competing SGR events in individual patients. Our findings demonstrate that SGR is common in SAMD9/9Lmut MDS and exemplify the exceptional plasticity of hematopoiesis in children.

Published
2021

4. Publisher Correction: Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes (Nature Medicine, (2021), 27, 10, (1806-1817), 10.1038/s41591-021-01511-6)

Author

Sahoo, S. S., Pastor, V. B., Goodings, C., Voss, R. K., Kozyra, E. J., Szvetnik, A., Noellke, P., Dworzak, M., Stary, J., Locatelli, Franco, Masetti, R., Schmugge, M., De Moerloose, B., Catala, A., Kallay, K., Turkiewicz, D., Hasle, H., Buechner, J., Jahnukainen, K., Ussowicz, M., Polychronopoulou, S., Smith, O. P., Fabri, O., Barzilai, S., de Haas, V., Baumann, I., Schwarz-Furlan, S., Smith, O., Haas, V. D., Gohring, G., Niemeyer, C., Nebral, K., Simonitsch-Kluppp, I., Paepe, P. D., Van Roy, N., Campr, V., Zemanova, Z., Clasen-Linde, E., Plesner, T., Schlegelberger, B., Rudelius, M., Manola, K., Stefanaki, K., Csomor, J., Andrikovics, H., Betts, D., O'Sullivan, M., Zohar, Y., Jeison, M., Vito, R. D., Pasquali, F., Maldyk, J., Haus, O., Alaiz, H., Kjollerstrom, P., Lemos, L. M., Bodova, I., Cermak, M., Plank, L., Gazic, B., Kavcic, M., Podgornik, H., Ros, M. L., Cervera, J., Gengler, C., Tchinda, J., Beverloo, B., Leguit, R., Niewisch, M. R., Sauer, M. G., Burkhardt, B., Lang, P., Bader, P., Beier, R., Muller, I., Albert, M. H., Meisel, R., Schulz, A., Cario, G., Panda, P. K., Wehrle, J., Hirabayashi, S., Derecka, M., Durruthy-Durruthy, R., Yoshimi-Noellke, A., Ku, M., Lebrecht, D., Erlacher, M., Flotho, C., Strahm, B., Niemeyer, C. M., Wlodarski, M. W., Locatelli F. (ORCID:0000-0002-7976-3654), Sahoo, S. S., Pastor, V. B., Goodings, C., Voss, R. K., Kozyra, E. J., Szvetnik, A., Noellke, P., Dworzak, M., Stary, J., Locatelli, Franco, Masetti, R., Schmugge, M., De Moerloose, B., Catala, A., Kallay, K., Turkiewicz, D., Hasle, H., Buechner, J., Jahnukainen, K., Ussowicz, M., Polychronopoulou, S., Smith, O. P., Fabri, O., Barzilai, S., de Haas, V., Baumann, I., Schwarz-Furlan, S., Smith, O., Haas, V. D., Gohring, G., Niemeyer, C., Nebral, K., Simonitsch-Kluppp, I., Paepe, P. D., Van Roy, N., Campr, V., Zemanova, Z., Clasen-Linde, E., Plesner, T., Schlegelberger, B., Rudelius, M., Manola, K., Stefanaki, K., Csomor, J., Andrikovics, H., Betts, D., O'Sullivan, M., Zohar, Y., Jeison, M., Vito, R. D., Pasquali, F., Maldyk, J., Haus, O., Alaiz, H., Kjollerstrom, P., Lemos, L. M., Bodova, I., Cermak, M., Plank, L., Gazic, B., Kavcic, M., Podgornik, H., Ros, M. L., Cervera, J., Gengler, C., Tchinda, J., Beverloo, B., Leguit, R., Niewisch, M. R., Sauer, M. G., Burkhardt, B., Lang, P., Bader, P., Beier, R., Muller, I., Albert, M. H., Meisel, R., Schulz, A., Cario, G., Panda, P. K., Wehrle, J., Hirabayashi, S., Derecka, M., Durruthy-Durruthy, R., Yoshimi-Noellke, A., Ku, M., Lebrecht, D., Erlacher, M., Flotho, C., Strahm, B., Niemeyer, C. M., Wlodarski, M. W., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

In the version of this Article initially published, there were errors in Fig. 1. Specifically, in the top right box in Fig. 1a, the text now reading “n = 25” mistakenly read “125” in the original publication. Further, in the four graphs of Fig. 1e, the colored labels “Wild-type,” “SAMD9/9Lmut” and “GATA2mut” were misaligned to the n and P values at their right. These errors have been corrected in the online version of the article.

Published
2021

5. Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial.

Author

Male, C., Lensing, A.W.A., Palumbo, J.S., Kumar, R., Nurmeev, I., Hege, K., Bonnet, D., Connor, P., Hooimeijer, H.L., Torres, M., Chan, A.K., Kenet, G., Holzhauer, S., Santamaria, A., Amedro, P., Chalmers, E., Simioni, P., Bhat, R.V., Yee, D.L., Lvova, O., Beyer-Westendorf, J., Biss, T.T., Martinelli, I., Saracco, P., Peters, M., Kallay, K., Gauger, C.A., Massicotte, M.P., Young, G., Pap, A.F., Majumder, M., Smith, W.T., Heubach, J.F., Berkowitz, S.D., Thelen, K., Kubitza, D., Crowther, M., Loo, D.M.W.M. te, Prins, M.H, Monagle, P., Male, C., Lensing, A.W.A., Palumbo, J.S., Kumar, R., Nurmeev, I., Hege, K., Bonnet, D., Connor, P., Hooimeijer, H.L., Torres, M., Chan, A.K., Kenet, G., Holzhauer, S., Santamaria, A., Amedro, P., Chalmers, E., Simioni, P., Bhat, R.V., Yee, D.L., Lvova, O., Beyer-Westendorf, J., Biss, T.T., Martinelli, I., Saracco, P., Peters, M., Kallay, K., Gauger, C.A., Massicotte, M.P., Young, G., Pap, A.F., Majumder, M., Smith, W.T., Heubach, J.F., Berkowitz, S.D., Thelen, K., Kubitza, D., Crowther, M., Loo, D.M.W.M. te, Prins, M.H, and Monagle, P.

Abstract

1 januari 2020, Contains fulltext : 219893.pdf (Publisher’s version ) (Closed access), BACKGROUND: Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism. METHODS: In a multicentre, parallel-group, open-label, randomised study, children (aged 0-17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children <2 years of age with catheter-related venous thromboembolism). The primary efficacy outcome, symptomatic recurrent venous thromboembolism (assessed by intention-to-treat), and the principal safety outcome, major or clinically relevant non-major bleeding (assessed in participants who received >/=1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed. FINDINGS: From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87-95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29-35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0.40, 95% CI 0.11-1.41). Repeat imaging showed an improved e

Published
2020

6. Safety and efficacy of rivaroxaban in pediatric cerebral venous thrombosis (EINSTEIN-Jr CVT)

Author

Connor, P, van Kammen, MS, Lensing, AWA, Chalmers, E, Kallay, K, Hege, K, Simioni, P, Biss, T, Bajolle, F, Bonnet, D, Grunt, S, Kumar, R, Lvova, O, Bhat, R, Van Damme, A, Palumbo, J, Santamaria, A, Saracco, P, Payne, J, Baird, S, Godder, K, Labarque, V, Male, C, Martinelli, I, Soto, MM, Motwani, J, Shah, S, Hooimeijer, HL, Prins, MH, Kubitza, D, Smith, WT, Berkowitz, SD, Pap, AF, Majumder, M, Monagle, P, Coutinho, JM, Connor, P, van Kammen, MS, Lensing, AWA, Chalmers, E, Kallay, K, Hege, K, Simioni, P, Biss, T, Bajolle, F, Bonnet, D, Grunt, S, Kumar, R, Lvova, O, Bhat, R, Van Damme, A, Palumbo, J, Santamaria, A, Saracco, P, Payne, J, Baird, S, Godder, K, Labarque, V, Male, C, Martinelli, I, Soto, MM, Motwani, J, Shah, S, Hooimeijer, HL, Prins, MH, Kubitza, D, Smith, WT, Berkowitz, SD, Pap, AF, Majumder, M, Monagle, P, and Coutinho, JM

Abstract

Anticoagulant treatment of pediatric cerebral venous thrombosis has not been evaluated in randomized trials. We evaluated the safety and efficacy of rivaroxaban and standard anticoagulants in the predefined subgroup of children with cerebral venous thrombosis (CVT) who participated in the EINSTEIN-Jr trial. Children with CVT were randomized (2:1), after initial heparinization, to treatment with rivaroxaban or standard anticoagulants (continued on heparin or switched to vitamin K antagonist). The main treatment period was 3 months. The primary efficacy outcome, symptomatic recurrent venous thromboembolism (VTE), and principal safety outcome, major or clinically relevant nonmajor bleeding,were centrally evaluated by blinded investigators. Sinus recanalization on repeat brain imaging was a secondary outcome. Statistical analyses were exploratory. In total, 114 children with confirmed CVT were randomized. All children completed the follow-up. None of the 73 rivaroxaban recipients and 1 (2.4%; CVT) of the 41 standard anticoagulant recipients had symptomatic, recurrent VTE after 3 months (absolute difference, 2.4%; 95% confidence interval [CI], -2.6% to 13.5%). Clinically relevant bleeding occurred in 5 (6.8%; all nonmajor and noncerebral) rivaroxaban recipients and in 1 (2.5%; major [subdural] bleeding) standard anticoagulant recipient (absolute difference, 4.4%; 95% CI, -6.7% to 13.4%). Complete or partial sinus recanalization occurred in 18 (25%) and 39 (53%) rivaroxaban recipients and in 6 (15%) and 24 (59%) standard anticoagulant recipients, respectively. In summary, in this substudy of a randomized trial with a limited sample size, children with CVT treated with rivaroxaban or standard anticoagulation had a low risk of recurrent VTE and clinically relevant bleeding. This trial was registered at clinicaltrials.gov as #NCT02234843.

Published
2020

7. Synonymous GATA2 mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency

Author

Kozyra, E. J., Pastor, V. B., Lefkopoulos, S., Sahoo, S. S., Busch, H., Voss, R. K., Erlacher, M., Lebrecht, D., Szvetnik, E. A., Hirabayashi, S., Pasauliene, R., Pedace, L., Tartaglia, M., Klemann, C., Metzger, P., Boerries, M., Catala, A., Hasle, H., de Haas, V., Kallay, K., Masetti, R., De Moerloose, B., Dworzak, M., Schmugge, M., Smith, O., Stary, J., Mejstrikova, E., Ussowicz, M., Morris, E., Singh, P., Collin, M., Derecka, M., Gohring, G., Flotho, C., Strahm, B., Locatelli, Franco, Niemeyer, C. M., Trompouki, E., Wlodarski, M. W., Locatelli F. (ORCID:0000-0002-7976-3654), Kozyra, E. J., Pastor, V. B., Lefkopoulos, S., Sahoo, S. S., Busch, H., Voss, R. K., Erlacher, M., Lebrecht, D., Szvetnik, E. A., Hirabayashi, S., Pasauliene, R., Pedace, L., Tartaglia, M., Klemann, C., Metzger, P., Boerries, M., Catala, A., Hasle, H., de Haas, V., Kallay, K., Masetti, R., De Moerloose, B., Dworzak, M., Schmugge, M., Smith, O., Stary, J., Mejstrikova, E., Ussowicz, M., Morris, E., Singh, P., Collin, M., Derecka, M., Gohring, G., Flotho, C., Strahm, B., Locatelli, Franco, Niemeyer, C. M., Trompouki, E., Wlodarski, M. W., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Deficiency of the transcription factor GATA2 is a highly penetrant genetic disorder predisposing to myelodysplastic syndromes (MDS) and immunodeficiency. It has been recognized as the most common cause underlying primary MDS in children. Triggered by the discovery of a recurrent synonymous GATA2 variant, we systematically investigated 911 patients with phenotype of pediatric MDS or cellular deficiencies for the presence of synonymous alterations in GATA2. In total, we identified nine individuals with five heterozygous synonymous mutations: c.351C>G, p.T117T (N = 4); c.649C>T, p.L217L; c.981G>A, p.G327G; c.1023C>T, p.A341A; and c.1416G>A, p.P472P (N = 2). They accounted for 8.2% (9/110) of cases with GATA2 deficiency in our cohort and resulted in selective loss of mutant RNA. While for the hotspot mutation (c.351C>G) a splicing error leading to RNA and protein reduction was identified, severe, likely late stage RNA loss without splicing disruption was found for other mutations. Finally, the synonymous mutations did not alter protein function or stability. In summary, synonymous GATA2 substitutions are a new common cause of GATA2 deficiency. These findings have broad implications for genetic counseling and pathogenic variant discovery in Mendelian disorders.

Published
2020

8. Results of allogeneic stem cell transplantation in patients affected by Shwachman-Diamond syndrome. A retrospective study of SAA-EBMT

Author

Cesaro, Simone, Gloria, Tridello, Christian, Kratz, Marta, Pillon, Halkes, S, Edoardo, Lanino, Regis Peffault De Latour, C Diaz De Heredia, Robert, Wynn, Johann, Greil, Franco, Locatelli, Paul, Veys, Anne, Uyttebroeck, Per, Ljungman, Patrice, Chevalier, Marc, Ansari, Isabel, Badell, Tayfun, Gungor, Salim, Rahuman, Johanna, Tischer, Tecchio, Cristina, Nigel, Russel, Alicja, Chybicka, Kallay, K, Owen, Smith, Afanasyev, B, Stein, J, Jan, Styczynski, Paul, Bosman, and Carlo, Dufour.

Subjects
Shwachman Diamond Disease, stem cell transplantation, survival, stem cell transplantation, survival, Shwachman Diamond Disease
Published
2018

9. Comparative study of two antihypertensive agents: guanfacine and guanethidine.

Author

Szam, I. and Kallay, K.

Abstract

1. The antihypertensive effect and side-effects of the new centrally acting agent guanfacine (BS 100-141, Estulic) and guanethidine (Ismelin) were compared in a single-blind, cross-over study. The study consisted of two active treatment periods of 6 weeks each, both preceded by a 1-3 weeks placebo period. 2. Sixteen ambulant patients (six male, ten female) with mild or moderate hypertension were admitted to the study. The patients were also receiving diuretic therapy (clopamide 10-20 mg daily). On average the optimal daily dose of guanfacine was 3 mg and of guanethidine 20 mg. 3. An equally large and significant decrease in blood pressure was produced by both drugs. Both guanfacine and guanethidine caused a very slight reduction in heart rate. Mild orthostatic hypotension occurred in 11 patients during guanethidine therapy. Dryness of the mouth occurred in 13 patients taking guanfacine. [ABSTRACT FROM AUTHOR]

Published
1980
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10. Synonymous GATA2 mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency

Author

Matthew Collin, Dirk Lebrecht, Eirini Trompouki, Emilia J Kozyra, Brigitte Strahm, Valerie de Haas, Sushree S. Sahoo, Owen P. Smith, Riccardo Masetti, Christian Flotho, Charlotte M. Niemeyer, Marta Derecka, Marco Tartaglia, Markus Schmugge, Krisztián Kállay, Rebecca K Voss, Henrik Hasle, Miriam Erlacher, Christian Klemann, Gudrun Göhring, Ester Mejstrikova, Marek Ussowicz, Hauke Busch, Preeti Singh, Barbara De Moerloose, Enikoe Amina Szvetnik, Marcin W. Wlodarski, Patrick Metzger, Lucia Pedace, Shinsuke Hirabayashi, Michael Dworzak, Emma C. Morris, Albert Català, Ramunė Pasaulienė, Jan Starý, Stylianos Lefkopoulos, Franco Locatelli, Victor B Pastor, Melanie Boerries, Kozyra E.J., Pastor V.B., Lefkopoulos S., Sahoo S.S., Busch H., Voss R.K., Erlacher M., Lebrecht D., Szvetnik E.A., Hirabayashi S., Pasauliene R., Pedace L., Tartaglia M., Klemann C., Metzger P., Boerries M., Catala A., Hasle H., de Haas V., Kallay K., Masetti R., De Moerloose B., Dworzak M., Schmugge M., Smith O., Stary J., Mejstrikova E., Ussowicz M., Morris E., Singh P., Collin M., Derecka M., Gohring G., Flotho C., Strahm B., Locatelli F., Niemeyer C.M., Trompouki E., and Wlodarski M.W.

Subjects
Male, Cancer Research, GATA2 Deficiency, VARIANT, WORLD-HEALTH-ORGANIZATION, GATA-2, Exon, Genetics research, Medicine and Health Sciences, MDS, TRANSCRIPTION, Child, Exome, Genetics, GATA2, RNA, Genetic disorder, Hematology, ABSENCE, REVISION, GATA2 Transcription Factor, DIFFERENTIATION, Phenotype, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Oncology, Child, Preschool, RNA splicing, Female, Synonymous substitution, Haematological diseases, EXPRESSION, Silent mutation, Adult, Heterozygote, Adolescent, Biology, CLASSIFICATION, Article, Young Adult, Germline mutation, GATA2 mutations, children, myelodysplastic syndromes, medicine, Humans, Genetic Predisposition to Disease, MYELOID NEOPLASMS, Genetic Association Studies, Germ-Line Mutation, Silent Mutation, Immunologic Deficiency Syndromes, medicine.disease, Myelodysplastic Syndromes, LEUKEMIA
Abstract

Deficiency of the transcription factor GATA2 is a highly penetrant genetic disorder predisposing to myelodysplastic syndromes (MDS) and immunodeficiency. It has been recognized as the most common cause underlying primary MDS in children. Triggered by the discovery of a recurrent synonymous GATA2 variant, we systematically investigated 911 patients with phenotype of pediatric MDS or cellular deficiencies for the presence of synonymous alterations in GATA2. In total, we identified nine individuals with five heterozygous synonymous mutations: c.351C>G, p.T117T (N = 4); c.649C>T, p.L217L; c.981G>A, p.G327G; c.1023C>T, p.A341A; and c.1416G>A, p.P472P (N = 2). They accounted for 8.2% (9/110) of cases with GATA2 deficiency in our cohort and resulted in selective loss of mutant RNA. While for the hotspot mutation (c.351C>G) a splicing error leading to RNA and protein reduction was identified, severe, likely late stage RNA loss without splicing disruption was found for other mutations. Finally, the synonymous mutations did not alter protein function or stability. In summary, synonymous GATA2 substitutions are a new common cause of GATA2 deficiency. These findings have broad implications for genetic counseling and pathogenic variant discovery in Mendelian disorders.

Published
2020
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