%0 Journal Article
%T Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes
%A Berivan Baskin
%A Bruce D. Gelb
%A Cameron Mroske
%A Cesare Rossi
%A Deborah A. Nickerson
%A Douglas Larsen
%A Ehsan Amin
%A Elia Di Schiavi
%A Francesca Lepri
%A Francesca Pantaleoni
%A Guido Cocchi
%A Ivan Gallotta
%A Jessica X. Chong
%A Katelyn Payne
%A Katherine G. Langley
%A Kathleen Brown
%A Kazem Nouri
%A Kelly D. Farwell
%A Laurence Walsh
%A Licia Lugli
%A Lindsay Henderson
%A Luca Pannone
%A Luciapia Farina
%A Lucie Dupuis
%A Marcel Buchholzer
%A Marco Seri
%A Marco Tartaglia
%A Maria Cristina Digilio
%A Mari£¿lle Alders
%A Martin Zenker
%A Mary Ella Pierpont
%A Matteo della Monica
%A Megan T. Cho
%A Michael J. Bamshad
%A Mohammad Reza Ahmadian
%A Naomi Meeks
%A Oliver H.F. Krumbach
%A Radovan Dvorsky
%A Raoul C. Hennekam
%A Raphael Konopatzki
%A Roberto Mendoza-Londono
%A Samantha Schrier Vergano
%A Sha Tang
%A Simona Coppola
%A Simone Martinelli
%A Stephanie Demuth
%A Tahnee Causey
%A The University of Washington Center for Mendelian Genomics
%J Archive of "American Journal of Human Genetics".
%D 2018
%R 10.1016/j.ajhg.2017.12.015
%X 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
%K exome sequencing
%K mutation spectrum
%K functional profiling
%K developmental anomalies
%K phenotypic heterogeneity
%K genotype-phenotype correlations
%K thrombocytopenia
%K Noonan syndrome
%K microcephaly
%K cardiac defects
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985417/