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Novel Association of Neurofibromatosis Type 1-Causing Mutations in Families With Neurofibromatosis-Noonan Syndrome

Ekvall, Sara; Sjors, Kerstin; Jonzon, Anders; Vihinen, Mauno LU ; Anneren, Goran and Bondeson, Marie-Louise (2014) In American Journal of Medical Genetics. Part A 164(3). p.579-587
Abstract
Neurofibromatosis-Noonan syndrome (NFNS) is a rare condition with clinical features of both neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). All three syndromes belong to the RASopathies, which are caused by dysregulation of the RAS-MAPK pathway. The major gene involved in NFNS is NF1, but co-occurring NF1 and PTPN11 mutations in NFNS have been reported. Knowledge about possible involvement of additional RASopathy-associated genes in NFNS is, however, very limited. We present a comprehensive clinical and molecular analysis of eight affected individuals from three unrelated families displaying features of NF1 and NFNS. The genetic etiology of the clinical phenotypes was investigated by mutation analysis, including NF1, PTPN11, SOS1,... (More)
Neurofibromatosis-Noonan syndrome (NFNS) is a rare condition with clinical features of both neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). All three syndromes belong to the RASopathies, which are caused by dysregulation of the RAS-MAPK pathway. The major gene involved in NFNS is NF1, but co-occurring NF1 and PTPN11 mutations in NFNS have been reported. Knowledge about possible involvement of additional RASopathy-associated genes in NFNS is, however, very limited. We present a comprehensive clinical and molecular analysis of eight affected individuals from three unrelated families displaying features of NF1 and NFNS. The genetic etiology of the clinical phenotypes was investigated by mutation analysis, including NF1, PTPN11, SOS1, KRAS, NRAS, BRAF, RAF1, SHOC2, SPRED1, MAP2K1, MAP2K2, and CBL. All three families harbored a heterozygous NF1 variant, where the first family had a missense variant, c.5425C>T;p.R1809C, the second family a recurrent 4bp-deletion, c.6789_6792delTTAC;p.Y2264Tfs*6, and the third family a splice-site variant, c.2991-1G>A, resulting in skipping of exon 18 and an in-frame deletion of 41 amino acids. These NF1 variants have all previously been reported in NF1 patients. Surprisingly, both c.6789_6792delTTAC and c.2991-1G>A are frequently associated with NF1, but association to NFNS has, to our knowledge, not previously been reported. Our results support the notion that NFNS represents a variant of NF1, genetically distinct from NS, and is caused by mutations in NF1, some of which also cause classical NF1. Due to phenotypic overlap between NFNS and NS, we propose screening for NF1 mutations in NS patients, preferentially when cafe-au-lait spots are present. (c) 2013 Wiley Periodicals, Inc. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
NF1, neurofibromatosis type 1, neurofibromatosis-Noonan syndrome, mutation, RAS-MAPK pathway, RASopathies
in
American Journal of Medical Genetics. Part A
volume
164
issue
3
pages
579 - 587
publisher
John Wiley & Sons
external identifiers
  • wos:000331978700002
  • scopus:84894244169
ISSN
1552-4825
DOI
10.1002/ajmg.a.36313
language
English
LU publication?
yes
id
c330bec8-eb86-4682-afca-4482b6ffe819 (old id 4559479)
date added to LUP
2014-08-01 07:44:19
date last changed
2017-06-25 03:04:38
@article{c330bec8-eb86-4682-afca-4482b6ffe819,
  abstract     = {Neurofibromatosis-Noonan syndrome (NFNS) is a rare condition with clinical features of both neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). All three syndromes belong to the RASopathies, which are caused by dysregulation of the RAS-MAPK pathway. The major gene involved in NFNS is NF1, but co-occurring NF1 and PTPN11 mutations in NFNS have been reported. Knowledge about possible involvement of additional RASopathy-associated genes in NFNS is, however, very limited. We present a comprehensive clinical and molecular analysis of eight affected individuals from three unrelated families displaying features of NF1 and NFNS. The genetic etiology of the clinical phenotypes was investigated by mutation analysis, including NF1, PTPN11, SOS1, KRAS, NRAS, BRAF, RAF1, SHOC2, SPRED1, MAP2K1, MAP2K2, and CBL. All three families harbored a heterozygous NF1 variant, where the first family had a missense variant, c.5425C>T;p.R1809C, the second family a recurrent 4bp-deletion, c.6789_6792delTTAC;p.Y2264Tfs*6, and the third family a splice-site variant, c.2991-1G>A, resulting in skipping of exon 18 and an in-frame deletion of 41 amino acids. These NF1 variants have all previously been reported in NF1 patients. Surprisingly, both c.6789_6792delTTAC and c.2991-1G>A are frequently associated with NF1, but association to NFNS has, to our knowledge, not previously been reported. Our results support the notion that NFNS represents a variant of NF1, genetically distinct from NS, and is caused by mutations in NF1, some of which also cause classical NF1. Due to phenotypic overlap between NFNS and NS, we propose screening for NF1 mutations in NS patients, preferentially when cafe-au-lait spots are present. (c) 2013 Wiley Periodicals, Inc.},
  author       = {Ekvall, Sara and Sjors, Kerstin and Jonzon, Anders and Vihinen, Mauno and Anneren, Goran and Bondeson, Marie-Louise},
  issn         = {1552-4825},
  keyword      = {NF1,neurofibromatosis type 1,neurofibromatosis-Noonan syndrome,mutation,RAS-MAPK pathway,RASopathies},
  language     = {eng},
  number       = {3},
  pages        = {579--587},
  publisher    = {John Wiley & Sons},
  series       = {American Journal of Medical Genetics. Part A},
  title        = {Novel Association of Neurofibromatosis Type 1-Causing Mutations in Families With Neurofibromatosis-Noonan Syndrome},
  url          = {http://dx.doi.org/10.1002/ajmg.a.36313},
  volume       = {164},
  year         = {2014},
}