Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes

Simone Martinelli, Oliver H. F. Krumbach, Francesca Pantaleoni, Simona Coppola, Ehsan Amin, Luca Pannone, Kazem Nouri, Luciapia Farina, Radovan Dvorsky, Francesca Lepri, Marcel Buchholzer, Raphael Konopatzki, Laurence Walsh, Katelyn Payne, Mary Ella Pierpont, Samantha Schrier Vergano, Katherine G. Langley, Douglas Larsen, Kelly D. Farwell, Sha TangCameron Mroske, Ivan Gallotta, Elia Di Schiavi, Matteo Della Monica, Licia Lugli, Cesare Rossi, Marco Seri, Guido Cocchi, Lindsay Henderson, Berivan Baskin, Mariëlle Alders, Roberto Mendoza-Londono, Lucie Dupuis, Deborah A. Nickerson, Jessica X. Chong, Naomi Meeks, Kathleen Brown, Tahnee Causey, Megan T. Cho, Stephanie Demuth, Maria Cristina Digilio, Bruce D. Gelb, Michael J. Bamshad, Martin Zenker, Mohammad Reza Ahmadian, Raoul C. Hennekam, Marco Tartaglia, Ghayda M. Mirzaa

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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
Pages (from-to)309-320
JournalAmerican journal of human genetics
Issue number2
Publication statusPublished - 2018

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