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Eur J Hum Genet. 2017 Jun;25(7):823-831. doi: 10.1038/ejhg.2017.65. Epub 2017 May 3.

Genotype and phenotype spectrum of NRAS germline variants.

Author information

1
Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.
2
RG Presynaptic Plasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.
3
Unidade de Genética do Instituto da Criança-Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
4
Centro de Pesquisa sobre o Genoma Humano e Células-Tronco - Instituto de Biociências da Universidade de São Paulo, São Paulo, Brazil.
5
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
6
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia.
7
Praxis für Humangenetik, Bremen, Germany.
8
Genetic Services of Western Australia, WA Department of Health, Perth, Western Australia, Australia.
9
School of Paediatrics and Child Health, Perth, Western Australia, Australia.
10
Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia.
11
Office of Population Health Genomics, Public Health and Clinical Services Division, WA Department of Health, Perth, Western Australia, Australia.
12
Telethon Kids Institute, Perth, Western Australia, Australia.
13
Western Australian Register of Developmental Anomalies, WA Department of Health, Perth, Western Australia, Australia.
14
Spatial Sciences, Department of Science and Engineering, Curtin University, Perth, Western Australia, Australia.
15
Department of Paediatrics and Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
16
Department of Pediatrics, University of British Columbia, Division of Biochemical Diseases, BC Children's Hospital, Vancouver, British Columbia, Canada.
17
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
18
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy.
19
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
20
Maritime Medical Genetics Service, IWK Health Centre, Halifax, Nova Scotia, Canada.
21
Department of Diagnostic Genomics, PathWest Laboratory Medicine WA, Perth, Western Australia, Australia.
22
School of Pathology and Laboratory Medicine, The University of Western Australia, Perth, Western Australia, Australia.
23
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
24
Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
25
Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany.
26
Instituto de Genética Médica y Molecular, Hospital Universitario La Paz, Madrid, Spain.
27
Unidad de Hemato-Oncología Pediátrica, Hospital Universitario La Paz, Madrid, Spain.
28
Institute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich Heine University, Düsseldorf, Germany.
29
INSERM UMR_S1131, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris-Sorbonne-Cité, Paris, France.
30
Département de Génétique, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Paris, France.

Abstract

RASopathies comprise a group of disorders clinically characterized by short stature, heart defects, facial dysmorphism, and varying degrees of intellectual disability and cancer predisposition. They are caused by germline variants in genes encoding key components or modulators of the highly conserved RAS-MAPK signalling pathway that lead to dysregulation of cell signal transmission. Germline changes in the genes encoding members of the RAS subfamily of GTPases are rare and associated with variable phenotypes of the RASopathy spectrum, ranging from Costello syndrome (HRAS variants) to Noonan and Cardiofaciocutaneous syndromes (KRAS variants). A small number of RASopathy cases with disease-causing germline NRAS alterations have been reported. Affected individuals exhibited features fitting Noonan syndrome, and the observed germline variants differed from the typical oncogenic NRAS changes occurring as somatic events in tumours. Here we describe 19 new cases with RASopathy due to disease-causing variants in NRAS. Importantly, four of them harbored missense changes affecting Gly12, which was previously described to occur exclusively in cancer. The phenotype in our cohort was variable but well within the RASopathy spectrum. Further, one of the patients (c.35G>A; p.(Gly12Asp)) had a myeloproliferative disorder, and one subject (c.34G>C; p.(Gly12Arg)) exhibited an uncharacterized brain tumour. With this report, we expand the genotype and phenotype spectrum of RASopathy-associated germline NRAS variants and provide evidence that NRAS variants do not spare the cancer-associated mutation hotspots.

PMID:
28594414
PMCID:
PMC5520077
DOI:
10.1038/ejhg.2017.65
[Indexed for MEDLINE]
Free PMC Article

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