Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7
| Autor: | Brigitte Schlegelberger, Melanie Boerries, Ulf Tedgård, Brigitte Strahm, Gerhard Ehninger, Miriam Erlacher, John C. Achermann, Matthias Voss, Hauke Busch, Jochen Hochrein, Irith Baumann, Victor B Pastor, Lennart Nilsson, Marena R. Niewisch, Yenan T. Bryceson, Dirk Lebrecht, Jessica Boklan, Georg C. Schwabe, Ebru Tugrul Saribeyoglu, Charlotte M. Niemeyer, Henrik Hasle, Sushree Sangita Sahoo, Akiko Shimamura, Marcin W. Wlodarski |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Oncology Adult Male medicine.medical_specialty Adolescent Penetrance Tumor Suppressor Proteins/genetics Article 03 medical and health sciences Young Adult 0302 clinical medicine Internal medicine Medicine Humans Allele Child Allele frequency Myelodysplastic Syndromes/genetics Chromosome 7 (human) Family Health business.industry Myelodysplastic syndromes Tumor Suppressor Proteins Bone marrow failure Infant Hematology medicine.disease Thrombocytopenia 3. Good health Pedigree Leukemia 030104 developmental biology 030220 oncology & carcinogenesis Myelodysplastic Syndromes Child Preschool Female Chromosome Deletion business Haploinsufficiency Chromosomes Human Pair 7 |
| Zdroj: | Haematologica Pastor, V B, Sahoo, S, Boklan, J, Schwabe, G C, Saribeyoglu, E, Strahm, B, Lebrecht, D, Voss, M, Bryceson, Y T, Erlacher, M, Ehninger, G, Niewisch, M, Schlegelberger, B, Baumann, I, Achermann, J C, Shimamura, A, Hochrein, J, Tedgård, U, Nilsson, L, Hasle, H, Boerries, M, Busch, H, Niemeyer, C M & Wlodarski, M W 2018, ' Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7 ', Haematologica, vol. 103, no. 3, pp. 427-437 . https://doi.org/10.3324/haematol.2017.180778 |
| ISSN: | 1592-8721 0390-6078 |
| DOI: | 10.3324/haematol.2017.180778 |
| Popis: | Familial myelodysplastic syndromes arise from haploinsufficiency of genes involved in hematopoiesis and are primarily associated with early-onset disease. Here we describe a familial syndrome in seven patients from four unrelated pedigrees presenting with myelodysplastic syndrome and loss of chromosome 7/7q. Their median age at diagnosis was 2.1 years (range, 1-42). All patients presented with thrombocytopenia with or without additional cytopenias and a hypocellular marrow without an increase of blasts. Genomic studies identified constitutional mutations (p.H880Q, p.R986H, p.R986C and p.V1512M) in the SAMD9L gene on 7q21, with decreased allele frequency in hematopoiesis. The non-random loss of mutated SAMD9L alleles was attained via monosomy 7, deletion 7q, UPD7q, or acquired truncating SAMD9L variants p.R1188X and p.S1317RfsX21. Incomplete penetrance was noted in 30% (3/10) of mutation carriers. Long-term observation revealed divergent outcomes with either progression to leukemia and/or accumulation of driver mutations (n=2), persistent monosomy 7 (n=4), and transient monosomy 7 followed by spontaneous recovery with SAMD9L-wildtype UPD7q (n=2). Dysmorphic features or neurological symptoms were absent in our patients, pointing to the notion that myelodysplasia with monosomy 7 can be a sole manifestation of SAMD9L disease. Collectively, our results define a new subtype of familial myelodysplastic syndrome and provide an explanation for the phenomenon of transient monosomy 7. Registered at: www.clinicaltrials.gov; #NCT00047268. |
| Databáze: | OpenAIRE |
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