Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes

The University of Washington Center for Mendelian Genomics

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Exome sequencing has markedly enhanced the discovery of genes implicated in Mendelian disorders, particularly for individuals in whom a known clinical entity could not be assigned. This has led to the recognition that phenotypic heterogeneity resulting from allelic mutations occurs more commonly than previously appreciated. Here, we report that missense variants in CDC42, a gene encoding a small GTPase functioning as an intracellular signaling node, underlie a clinically heterogeneous group of phenotypes characterized by variable growth dysregulation, facial dysmorphism, and neurodevelopmental, immunological, and hematological anomalies, including a phenotype resembling Noonan syndrome, a developmental disorder caused by dysregulated RAS signaling. In silico, in vitro, and in vivo analyses demonstrate that mutations variably perturb CDC42 function by altering the switch between the active and inactive states of the GTPase and/or affecting CDC42 interaction with effectors, and differentially disturb cellular and developmental processes. These findings reveal the remarkably variable impact that dominantly acting CDC42 mutations have on cell function and development, creating challenges in syndrome definition, and exemplify the importance of functional profiling for syndrome recognition and delineation.

Original languageEnglish (US)
Pages (from-to)309-320
Number of pages12
JournalAmerican Journal of Human Genetics
Volume102
Issue number2
DOIs
StatePublished - Feb 1 2018

Keywords

  • Noonan syndrome
  • cardiac defects
  • developmental anomalies
  • exome sequencing
  • functional profiling
  • genotype-phenotype correlations
  • microcephaly
  • mutation spectrum
  • phenotypic heterogeneity
  • thrombocytopenia

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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