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. NiewischS. García-Miñaúr, D. Plaza, M.R. Ahmadian, H. Cavé, M. Tartaglia, M. Zenker

Research output: Contribution to journalArticlepeer-review

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. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Original languageEnglish
Pages (from-to)823-831
Number of pages9
JournalEuropean Journal of Human Genetics
Volume25
Issue number7
DOIs
Publication statusPublished - 2017

Keywords

  • glycine
  • n ras protein
  • Ras protein
  • unclassified drug
  • guanosine triphosphatase
  • membrane protein
  • NRAS protein, human
  • adolescent
  • adult
  • Article
  • brain tumor
  • child
  • clinical article
  • cohort analysis
  • female
  • genetic disorder
  • genetic variability
  • genotype
  • germline mutation
  • human
  • male
  • missense mutation
  • myeloproliferative disorder
  • oncogene N ras
  • phenotype
  • priority journal
  • RASopathy
  • congenital heart malformation
  • Costello syndrome
  • ectodermal dysplasia
  • facies
  • failure to thrive
  • genetics
  • infant
  • newborn
  • Noonan syndrome
  • pathology
  • preschool child
  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Costello Syndrome
  • Ectodermal Dysplasia
  • Facies
  • Failure to Thrive
  • Female
  • Genotype
  • Germ-Line Mutation
  • GTP Phosphohydrolases
  • Heart Defects, Congenital
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Membrane Proteins
  • Mutation, Missense
  • Noonan Syndrome
  • Phenotype

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