Genotype and phenotype spectrum of NRAS germline variants

Eur J Hum Genet. 2017 Jun;25(7):823-831. doi: 10.1038/ejhg.2017.65. Epub 2017 May 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Costello Syndrome / genetics*
  • Costello Syndrome / pathology
  • Ectodermal Dysplasia / genetics*
  • Ectodermal Dysplasia / pathology
  • Facies
  • Failure to Thrive / genetics*
  • Failure to Thrive / pathology
  • Female
  • GTP Phosphohydrolases / genetics*
  • Genotype
  • Germ-Line Mutation*
  • Heart Defects, Congenital / genetics*
  • Heart Defects, Congenital / pathology
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Membrane Proteins / genetics*
  • Mutation, Missense
  • Noonan Syndrome / genetics*
  • Noonan Syndrome / pathology
  • Phenotype

Substances

  • Membrane Proteins
  • GTP Phosphohydrolases
  • NRAS protein, human

Supplementary concepts

  • Cardiofaciocutaneous syndrome