Behavioral profile in RASopathies

Am J Med Genet A. 2014 Apr;164A(4):934-42. doi: 10.1002/ajmg.a.36374. Epub 2014 Jan 23.


Here, we describe neurobehavioral features in patients with RASopathies (i.e., Noonan syndrome, LEOPARD syndrome, Costello syndrome, and cardiofaciocutaneous syndrome), developmental disorders caused by mutations in genes coding transducers participating in the RAS-MAPK signaling cascade. Parents of 70 individuals with a RASopathy were asked to fill out the following questionnaires: Child Behavior Checklist (CBCL), Social Communication Questionnaire version lifetime (SCQ-L), and Modified Checklist for Autism in toddlers (M-CHAT). Data analysis indicated high rates of internalizing (37%) and externalizing problems (31%) on CBCL. Scores over the cut-off were documented in 64% of patients with cardiofaciocutaneous syndrome, 44% with Costello syndrome, and 12% with Noonan syndrome on SCQ-L/M-CHAT. Our findings indicate that mutations promoting dysregulation of the RAS-MAPK cascade mark an increased psychopathological risk and highlight that autistic-like behavior could be underdiagnosed in patients with RASopathies.

Keywords: Costello syndrome; LEOPARD syndrome; Noonan syndrome; Noonan-like syndrome with loose anagen hair; RAS/MAPK cascade; behavior; cardiofaciocutaneous syndrome; genotype-phenotype correlation analyses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Autistic Disorder / enzymology
  • Autistic Disorder / genetics
  • Child
  • Child, Preschool
  • Costello Syndrome / enzymology
  • Costello Syndrome / genetics
  • Developmental Disabilities / enzymology
  • Developmental Disabilities / genetics
  • Ectodermal Dysplasia / enzymology
  • Ectodermal Dysplasia / genetics
  • Facies
  • Failure to Thrive / enzymology
  • Failure to Thrive / genetics
  • Female
  • Heart Defects, Congenital / enzymology
  • Heart Defects, Congenital / genetics
  • Humans
  • LEOPARD Syndrome / enzymology
  • LEOPARD Syndrome / genetics
  • MAP Kinase Signaling System / genetics*
  • Male
  • Mental Disorders / enzymology*
  • Mental Disorders / genetics*
  • Mutation / genetics
  • Noonan Syndrome / enzymology
  • Noonan Syndrome / genetics
  • Young Adult
  • ras Proteins / genetics*


  • ras Proteins

Supplementary concepts

  • Cardiofaciocutaneous syndrome