Genotype and phenotype spectrum of NRAS germline variants

F. Altmüller; C. Lissewski; D. Bertola; E. Flex; Z. Stark; S. Spranger; G. Baynam; M. Buscarilli; S. Dyack; J. Gillis; H.G. Yntema; F. Pantaleoni; R.L.E. van Loon; S. MacKay; K. Mina; I. Schanze; T.Y. Tan; M. Walsh; S.M. White; M.R. Niewisch; S. García-Miñaúr; D. Plaza; M.R. Ahmadian; H. Cavé; M. Tartaglia; M. Zenker

doi:10.1038/ejhg.2017.65

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Genotype and phenotype spectrum of NRAS germline variants

Journal article

Peer reviewed

Genotype and phenotype spectrum of NRAS germline variants

F. Altmüller, C. Lissewski, D. Bertola, E. Flex, Z. Stark, S. Spranger, G. Baynam, M. Buscarilli, S. Dyack, J. Gillis, …

European Journal of Human Genetics, Vol.25(7), pp.823-831

2017

DOI: https://doi.org/10.1038/ejhg.2017.65

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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.

Details

Title: Genotype and phenotype spectrum of NRAS germline variants
Authors/Creators: F. Altmüller (Author/Creator) - Leibniz Institute for Neurobiology
C. Lissewski (Author/Creator) - University Hospital Magdeburg
D. Bertola (Author/Creator) - Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo
E. Flex (Author/Creator) - Istituto Superiore di Sanità
Z. Stark (Author/Creator) - Victorian Clinical Genetics Services
S. Spranger (Author/Creator) - Praxis für Humangenetik
G. Baynam (Author/Creator) - Government of Western Australia Department of Health
M. Buscarilli (Author/Creator) - Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo
S. Dyack (Author/Creator) - Dalhousie University
J. Gillis (Author/Creator) - University of British Columbia
H.G. Yntema (Author/Creator) - Radboud University Nijmegen
F. Pantaleoni (Author/Creator) - Bambino Gesù Children's Hospital
R.L.E. van Loon (Author/Creator) - Erasmus MC
S. MacKay (Author/Creator) - Izaak Walton Killam Health Centre
K. Mina (Author/Creator) - The University of Western Australia
I. Schanze (Author/Creator) - University Hospital Magdeburg
T.Y. Tan (Author/Creator) - The University of Melbourne
M. Walsh (Author/Creator) - Murdoch Children's Research Institute
S.M. White (Author/Creator) - The University of Melbourne
M.R. Niewisch (Author/Creator) - University of Freiburg
S. García-Miñaúr (Author/Creator) - Hospital Universitario La Paz
D. Plaza (Author/Creator) - Hospital Universitario La Paz
M.R. Ahmadian (Author/Creator) - Heinrich Heine University Düsseldorf
H. Cavé (Author/Creator) - Délégation Paris 7
M. Tartaglia (Author/Creator) - Bambino Gesù Children's Hospital
M. Zenker (Author/Creator) - University Hospital Magdeburg
Publication Details: European Journal of Human Genetics, Vol.25(7), pp.823-831
Publisher: Nature Publishing Group
Identifiers: 991005542113607891
Copyright: © Springer Nature.
Murdoch Affiliation: Institute for Immunology and Infectious Diseases
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.25 Molecular & Cell Biology - Cancer, Autophagy & Apoptosis; 1.25.1481 Phosphatases and Rasopathies
Web Of Science research areas: Biochemistry & Molecular Biology; Genetics & Heredity
ESI research areas: Molecular Biology & Genetics