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Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7

Pastor, Victor B.; Sahoo, Sushree S.; Boklan, Jessica; Schwabe, Georg C.; Saribeyoglu, Ebru; Strahm, Brigitte; Lebrecht, Dirk; Voss, Matthias; Bryceson, Yenan T. and Erlacher, Miriam, et al. (2018) In Haematologica 103(3). p.427-437
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 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... (More)

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.

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published
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in
Haematologica
volume
103
issue
3
pages
427 - 437
publisher
Ferrata Storti Foundation
external identifiers
  • scopus:85042784559
ISSN
0390-6078
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language
English
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no
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e9993e95-3763-45a9-9a75-8f2be2160127
date added to LUP
2018-04-12 13:47:16
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2018-06-10 05:28:13
@article{e9993e95-3763-45a9-9a75-8f2be2160127,
  abstract     = {<p>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.</p>},
  author       = {Pastor, Victor B. and Sahoo, Sushree S. and Boklan, Jessica and Schwabe, Georg C. and Saribeyoglu, Ebru and Strahm, Brigitte and Lebrecht, Dirk and Voss, Matthias and Bryceson, Yenan T. and Erlacher, Miriam and Ehninger, Gerhard and Niewisch, Marena and Schlegelberger, Brigitte and Baumann, Irith and Achermann, John C. and Shimamura, Akiko and Hochrein, Jochen and Tedgård, Ulf and Nilsson, Lars and Hasle, Henrik and Boerries, Melanie and Busch, Hauke and Niemeyer, Charlotte M. and Wlodarski, Marcin W.},
  issn         = {0390-6078},
  language     = {eng},
  month        = {02},
  number       = {3},
  pages        = {427--437},
  publisher    = {Ferrata Storti Foundation},
  series       = {Haematologica},
  title        = {Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7},
  url          = {http://dx.doi.org/},
  volume       = {103},
  year         = {2018},
}