The Arg1038Gly missense variant in the NF1 gene causes a mild phenotype without neurofibromas.
Arg1038Gly
Genotype-phenotype correlation
NF1
missense mutation
neurofibromatosis type 1
Journal
Molecular genetics & genomic medicine
ISSN: 2324-9269
Titre abrégé: Mol Genet Genomic Med
Pays: United States
ID NLM: 101603758
Informations de publication
Date de publication:
05 2019
05 2019
Historique:
received:
08
10
2018
revised:
16
01
2019
accepted:
11
02
2019
pubmed:
8
3
2019
medline:
27
6
2019
entrez:
8
3
2019
Statut:
ppublish
Résumé
Neurofibromatosis type 1 (NF1) is an autosomal dominant condition caused by inactivating mutations of the NF1 gene. The wide allelic heterogeneity of this condition, with more than 3,000 pathogenic variants reported so far, is paralleled by its high clinical variability, which is observed even within the same family. The definition of genotype-phenotype correlations has been hampered by the complexity of the NF1 gene and, although a few exceptions have been recognized, the clinical course remains unpredictable in most patients. Sequencing of NF1 in patients with cafè-au-lait spots identified the c.3112A>G variant. RNA analysis and a minigene assay were employed to investigate splicing. Here we report a novel genotype-phenotype correlation in NF1: the identification of the missense variant NM_000267.3:c.3112A>G p.(Arg1038Gly) in seven individuals from two unrelated families with a mild phenotype. All the patients manifest cafè-au-lait spots without neurofibromas or other NF1-associated complications, and Noonan syndrome features in most cases. The missense variant was not previously reported in available databases, segregates with the phenotype and involves a highly conserved residue. Both a minigene assay and patient's RNA analysis excluded an effect on splicing. Our data support the correlation of the p.Arg1038Gly missense substitution with the cutaneous phenotype without neurofibromas or other complications. This finding may have relevant implications for patients and genetic counseling, but also to get insights into the function of neurofibromin.
Sections du résumé
BACKGROUND
Neurofibromatosis type 1 (NF1) is an autosomal dominant condition caused by inactivating mutations of the NF1 gene. The wide allelic heterogeneity of this condition, with more than 3,000 pathogenic variants reported so far, is paralleled by its high clinical variability, which is observed even within the same family. The definition of genotype-phenotype correlations has been hampered by the complexity of the NF1 gene and, although a few exceptions have been recognized, the clinical course remains unpredictable in most patients.
METHODS
Sequencing of NF1 in patients with cafè-au-lait spots identified the c.3112A>G variant. RNA analysis and a minigene assay were employed to investigate splicing.
RESULTS
Here we report a novel genotype-phenotype correlation in NF1: the identification of the missense variant NM_000267.3:c.3112A>G p.(Arg1038Gly) in seven individuals from two unrelated families with a mild phenotype. All the patients manifest cafè-au-lait spots without neurofibromas or other NF1-associated complications, and Noonan syndrome features in most cases. The missense variant was not previously reported in available databases, segregates with the phenotype and involves a highly conserved residue. Both a minigene assay and patient's RNA analysis excluded an effect on splicing.
CONCLUSION
Our data support the correlation of the p.Arg1038Gly missense substitution with the cutaneous phenotype without neurofibromas or other complications. This finding may have relevant implications for patients and genetic counseling, but also to get insights into the function of neurofibromin.
Identifiants
pubmed: 30843352
doi: 10.1002/mgg3.616
pmc: PMC6503065
doi:
Substances chimiques
NF1 protein, human
0
Neurofibromin 1
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e616Subventions
Organisme : University of Padova
ID : CPDA140508/14
Pays : International
Informations de copyright
© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
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