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SAMD9 and SAMD9L in inherited predisposition to ataxia, pancytopenia, and myeloid malignancies

Davidsson, Josef LU ; Puschmann, Andreas LU ; Tedgård, Ulf LU ; Bryder, David LU ; Nilsson, Lars and Cammenga, Jörg (2018) In Leukemia 32(5). p.1106-1115
Abstract

Germline mutations in the SAMD9 and SAMD9L genes, located in tandem on chromosome 7, are associated with a clinical spectrum of disorders including the MIRAGE syndrome, ataxia–pancytopenia syndrome and myelodysplasia and leukemia syndrome with monosomy 7 syndrome. Germline gain-of-function mutations increase SAMD9 or SAMD9L’s normal antiproliferative effect. This causes pancytopenia and generally restricted growth and/or specific organ hypoplasia in non-hematopoietic tissues. In blood cells, additional somatic aberrations that reverse the germline mutation’s effect, and give rise to the clonal expansion of cells with reduced or no antiproliferative effect of SAMD9 or SAMD9L include complete or partial chromosome 7 loss or... (More)

Germline mutations in the SAMD9 and SAMD9L genes, located in tandem on chromosome 7, are associated with a clinical spectrum of disorders including the MIRAGE syndrome, ataxia–pancytopenia syndrome and myelodysplasia and leukemia syndrome with monosomy 7 syndrome. Germline gain-of-function mutations increase SAMD9 or SAMD9L’s normal antiproliferative effect. This causes pancytopenia and generally restricted growth and/or specific organ hypoplasia in non-hematopoietic tissues. In blood cells, additional somatic aberrations that reverse the germline mutation’s effect, and give rise to the clonal expansion of cells with reduced or no antiproliferative effect of SAMD9 or SAMD9L include complete or partial chromosome 7 loss or loss-of-function mutations in SAMD9 or SAMD9L. Furthermore, the complete or partial loss of chromosome 7q may cause myelodysplastic syndrome in these patients. SAMD9 mutations appear to associate with a more severe disease phenotype, including intrauterine growth restriction, developmental delay and hypoplasia of adrenal glands, testes, ovaries or thymus, and most reported patients died in infancy or early childhood due to infections, anemia and/or hemorrhages. SAMD9L mutations have been reported in a few families with balance problems and nystagmus due to cerebellar atrophy, and may lead to similar hematological disease as seen in SAMD9 mutation carriers, from early childhood to adult years. We review the clinical features of these syndromes, discuss the underlying biology, and interpret the genetic findings in some of the affected family members. We provide expert-based recommendations regarding diagnosis, follow-up, and treatment of mutation carriers.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
SAMD9, SAMD9L, Ataxia, myeloid malignancies
in
Leukemia
volume
32
issue
5
pages
1106 - 1115
publisher
Nature Publishing Group
external identifiers
  • scopus:85043686253
  • pmid:29535429
ISSN
0887-6924
DOI
10.1038/s41375-018-0074-4
language
English
LU publication?
yes
id
02d14a5a-b5da-4e83-a564-2f667643912b
date added to LUP
2018-03-26 15:59:19
date last changed
2019-04-10 04:05:23
@article{02d14a5a-b5da-4e83-a564-2f667643912b,
  abstract     = {<p>Germline mutations in the SAMD9 and SAMD9L genes, located in tandem on chromosome 7, are associated with a clinical spectrum of disorders including the MIRAGE syndrome, ataxia–pancytopenia syndrome and myelodysplasia and leukemia syndrome with monosomy 7 syndrome. Germline gain-of-function mutations increase SAMD9 or SAMD9L’s normal antiproliferative effect. This causes pancytopenia and generally restricted growth and/or specific organ hypoplasia in non-hematopoietic tissues. In blood cells, additional somatic aberrations that reverse the germline mutation’s effect, and give rise to the clonal expansion of cells with reduced or no antiproliferative effect of SAMD9 or SAMD9L include complete or partial chromosome 7 loss or loss-of-function mutations in SAMD9 or SAMD9L. Furthermore, the complete or partial loss of chromosome 7q may cause myelodysplastic syndrome in these patients. SAMD9 mutations appear to associate with a more severe disease phenotype, including intrauterine growth restriction, developmental delay and hypoplasia of adrenal glands, testes, ovaries or thymus, and most reported patients died in infancy or early childhood due to infections, anemia and/or hemorrhages. SAMD9L mutations have been reported in a few families with balance problems and nystagmus due to cerebellar atrophy, and may lead to similar hematological disease as seen in SAMD9 mutation carriers, from early childhood to adult years. We review the clinical features of these syndromes, discuss the underlying biology, and interpret the genetic findings in some of the affected family members. We provide expert-based recommendations regarding diagnosis, follow-up, and treatment of mutation carriers.</p>},
  author       = {Davidsson, Josef and Puschmann, Andreas and Tedgård, Ulf and Bryder, David and Nilsson, Lars and Cammenga, Jörg},
  issn         = {0887-6924},
  keyword      = {SAMD9,SAMD9L,Ataxia,myeloid malignancies},
  language     = {eng},
  number       = {5},
  pages        = {1106--1115},
  publisher    = {Nature Publishing Group},
  series       = {Leukemia},
  title        = {SAMD9 and SAMD9L in inherited predisposition to ataxia, pancytopenia, and myeloid malignancies},
  url          = {http://dx.doi.org/10.1038/s41375-018-0074-4},
  volume       = {32},
  year         = {2018},
}