Variability in clinical and neuropsychological features of individuals with MAP2K1 mutations

Elizabeth I. Pierpont, Margaret Semrud-Clikeman, Mary Ella Pierpont

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Mutations in MAP2K1, a gene expressed within the RAS-mitogen activated protein kinase (RAS/MAPK) pathway, are generally associated with the clinical phenotype of cardiofaciocutaneous syndrome. Here we describe two male patients (ages 16 and 20 years) with mutations in MAP2K1 and heterogeneous clinical presentations. Both young men had short stature, some facial features suggesting a RASopathy and minimal cardiac involvement. Detailed medical and neuropsychological findings are presented alongside a comprehensive review of features of patients with MAP2K1 mutations reported in the literature. Published studies have indicated that cognitive functioning of individuals with MAP2K1 mutations can range from severe intellectual disability to mildly below average. Neither of the individuals presented here had severe intellectual disability, and one had intellectual functioning within the average range. Neurodevelopmental concerns that were common among our two patients included fine motor difficulties, slow processing speed, reduced attention span, learning disabilities, and diminished energy/alertness. Taken together, our findings demonstrate that mutations in MAP2K1, which are frequently associated with neurological complications and intellectual disability, can be associated with a milder clinical and neurocognitive profile more typical of individuals with Noonan syndrome. Variability of expression may arise from a complex interplay between RAS/MAPK pathway genotype, epigenetics, medical and obstetric factors, and environmental influences.

Original languageEnglish (US)
Pages (from-to)452-459
Number of pages8
JournalAmerican Journal of Medical Genetics, Part A
Issue number2
StatePublished - Feb 1 2017

Bibliographical note

Publisher Copyright:
© 2016 Wiley Periodicals, Inc.


  • MAP2K1
  • MEK1
  • Noonan syndrome
  • RASopathies
  • behavior
  • cardiofaciocutanous syndrome
  • cognitive
  • neuropsychological
  • phenotype


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