Genotype and phenotype spectrum of NRAS germline variants

Franziska Altmüller, Christina Lissewski, Debora Bertola, Elisabetta Flex, Zornitza Stark, Stephanie Spranger, Gareth Baynam, Michelle Buscarilli, Sarah Dyack, Jane Gillis, Helger G. Yntema, Francesca Pantaleoni, Rosa L.E. Van Loon, Sara MacKay, Kym Mina, Ina Schanze, Tiong Yang Tan, Maie Walsh, Susan M. White, Marena R. NiewischSixto García-Miñaúr, Diego Plaza, Mohammad Reza Ahmadian, Hélène Cavé, Marco Tartaglia, Martin Zenker

Résultat de recherche: Articleexamen par les pairs

41 Citations (Scopus)

Résumé

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.

Langue d'origineEnglish
Pages (de-à)823-831
Nombre de pages9
JournalEuropean Journal of Human Genetics
Volume25
Numéro de publication7
DOI
Statut de publicationPublished - juin 1 2017

Note bibliographique

Funding Information:
This work was supported by E-Rare (NSEuroNet to MRA, HC, MT, and MZ), AIRC (IG17583 to MT), Italian Ministry of Health (RF-2011-02349938 and Ricerca Corrente 2016 to MT), Telethon (13107 to MT), German Federal Ministry of Education and Research (BMBF) NSEuroNet (FKZ 01GM1602A to MZ and MRA); GeNeRARe (FKZ 01GM1519A to MZ and MRA); Deutsche Forschungsgemeinschaft (ZE524/10-1 to MZ); LGS Synaptogenetics, CBBS to IS; Raine Clinician Research Fellowship to GB; Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) 2011/17299-3; 2013/08028-1 and Conselho Nacional de Pesquisa (CNPq) 304130/2016-8 to DB.

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

ASJC Scopus Subject Areas

  • Genetics
  • Genetics(clinical)

Empreinte numérique

Plonger dans les sujets de recherche 'Genotype and phenotype spectrum of NRAS germline variants'. Ensemble, ils forment une empreinte numérique unique.

Citer