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Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7

Pastor, VB; Sahoo, S; Boklan, J; Schwabe, GC; Saribeyoglu, E; Strahm, B; Lebrecht, D; ... Wlodarski, MW; + view all (2018) Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7. Haematologica , 103 (3) pp. 427-437. 10.3324/haematol.2017.180778. Green open access

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Abstract

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 7 patients from 4 unrelated pedigrees presenting with myelodisplastic syndrome and loss of chromosome 7/7q. Median age at diagnosis was 2.1 (1-42) years, all patients presented with thrombocytopenia with or without additional cytopenias and a hypocellular marrow without increase of blasts. Genomic studies identified constitutional mutations (p.H880Q, p.R986H, p.R986C and p.V1512M) in SAMD9L gene on 7q21, with decreased allele frequency in hematopoiesis. The nonrandom 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 leukemic progression 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 myelodisplasia with monosomy 7 can be a sole manifestation of SAMD9L disease. Collectively, our results define a new subtype of familial myelodisplastic syndrome and provide an explanation for the phenomenon of transient monosomy 7. www.clinicaltrials.gov; #NCT00047268.

Type: Article
Title: Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7
Location: Italy
Open access status: An open access version is available from UCL Discovery
DOI: 10.3324/haematol.2017.180778
Publisher version: http://doi.org/10.3324/haematol.2017.180778
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Bone Marrow Failure, Cytogenetics and Molecular Genetics, Hematopoiesis, Myelodysplastic Syndromes
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10040350
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