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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)823-831
Number of pages9
JournalEuropean Journal of Human Genetics
Volume25
Issue number7
DOIs
Publication statusPublished - Jun 1 2017

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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