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    Genotype and phenotype spectrum of NRAS germline variants

    Access Status
    Fulltext not available
    Authors
    Altmüller, F.
    Lissewski, C.
    Bertola, D.
    Flex, E.
    Stark, Z.
    Spranger, S.
    Baynam, Gareth
    Buscarilli, M.
    Dyack, S.
    Gillis, J.
    Yntema, H.
    Pantaleoni, F.
    Van Loon, R.
    MacKay, S.
    Mina, K.
    Schanze, I.
    Tan, T.
    Walsh, M.
    White, S.
    Niewisch, M.
    García-Miñaúr, S.
    Plaza, D.
    Ahmadian, M.
    Cavé, H.
    Tartaglia, M.
    Zenker, M.
    Date
    2017
    Type
    Journal Article
    
    Metadata
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    Citation
    Altmüller, F. and Lissewski, C. and Bertola, D. and Flex, E. and Stark, Z. and Spranger, S. and Baynam, G. et al. 2017. Genotype and phenotype spectrum of NRAS germline variants. European Journal of Human Genetics. 25 (7): pp. 823-831.
    Source Title
    European Journal of Human Genetics
    DOI
    10.1038/ejhg.2017.65
    ISSN
    1018-4813
    School
    School of Earth and Planetary Sciences (EPS)
    URI
    http://hdl.handle.net/20.500.11937/71161
    Collection
    • Curtin Research Publications
    Abstract

    © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. 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.

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