Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes

S. Martinelli, O.H.F. Krumbach, F. Pantaleoni, S. Coppola, E. Amin, L. Pannone, K. Nouri, L. Farina, R. Dvorsky, F. Lepri, M. Buchholzer, R. Konopatzki, L. Walsh, K. Payne, M.E. Pierpont, S.S. Vergano, K.G. Langley, D. Larsen, K.D. Farwell, S. TangC. Mroske, I. Gallotta, E. Di Schiavi, M. della Monica, L. Lugli, C. Rossi, M. Seri, G. Cocchi, L. Henderson, B. Baskin, M. Alders, R. Mendoza-Londono, L. Dupuis, D.A. Nickerson, J.X. Chong, N. Meeks, K. Brown, T. Causey, M.T. Cho, S. Demuth, M.C. Digilio, B.D. Gelb, M.J. Bamshad, M. Zenker, M.R. Ahmadian, R.C. Hennekam, M. Tartaglia, G.M. Mirzaa, The University of Washington Center for Mendelian Genomics

Research output: Contribution to journalArticlepeer-review


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. © 2017 American Society of Human Genetics
Original languageEnglish
Pages (from-to)309-320
Number of pages12
JournalAmerican Journal of Human Genetics
Issue number2
Publication statusPublished - 2018


  • cardiac defects
  • developmental anomalies
  • exome sequencing
  • functional profiling
  • genotype-phenotype correlations
  • microcephaly
  • mutation spectrum
  • Noonan syndrome
  • phenotypic heterogeneity
  • thrombocytopenia
  • arginine
  • binding protein
  • FMNL2 protein
  • glutamine
  • guanosine diphosphate
  • guanosine triphosphatase
  • guanosine triphosphate
  • IQ motif containing guanosine triphosphatase activating protein 1
  • p21 activated kinase 1
  • protein Cdc42
  • unclassified drug
  • Wiskott Aldrich syndrome protein
  • amino acid substitution
  • Article
  • CDC42 gene
  • child
  • clinical feature
  • cohort analysis
  • computer model
  • controlled study
  • DNA sequence
  • enzyme activity
  • gene overexpression
  • genetic variability
  • human
  • human cell
  • in vitro study
  • in vivo study
  • missense mutation
  • nucleotide transport
  • priority journal
  • protein binding
  • protein protein interaction
  • whole exome sequencing
  • wound healing assay


Dive into the research topics of 'Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes'. Together they form a unique fingerprint.

Cite this