Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes

• Published in: American journal of human genetics Vol. 102; no. 2; pp. 309 - 320
• Main Authors: Martinelli, Simone, Krumbach, Oliver H.F., Pantaleoni, Francesca, Coppola, Simona, Amin, Ehsan, Pannone, Luca, Nouri, Kazem, Farina, Luciapia, Dvorsky, Radovan, Lepri, Francesca, Buchholzer, Marcel, Konopatzki, Raphael, Walsh, Laurence, Payne, Katelyn, Pierpont, Mary Ella, Vergano, Samantha Schrier, Langley, Katherine G., Larsen, Douglas, Farwell, Kelly D., Tang, Sha, Mroske, Cameron, Gallotta, Ivan, Di Schiavi, Elia, della Monica, Matteo, Lugli, Licia, Rossi, Cesare, Seri, Marco, Cocchi, Guido, Henderson, Lindsay, Baskin, Berivan, Alders, Mariëlle, Mendoza-Londono, Roberto, Dupuis, Lucie, Nickerson, Deborah A., Chong, Jessica X., Meeks, Naomi, Brown, Kathleen, Causey, Tahnee, Cho, Megan T., Demuth, Stephanie, Digilio, Maria Cristina, Gelb, Bruce D., Bamshad, Michael J., Zenker, Martin, Ahmadian, Mohammad Reza, Hennekam, Raoul C., Tartaglia, Marco, Mirzaa, Ghayda M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2018; Elsevier
• Subjects: Abnormalities, Multiple - genetics; Abnormalities, Multiple - metabolism; Abnormalities, Multiple - pathology; Adolescent; Adult; cardiac defects; cdc42 GTP-Binding Protein - chemistry; cdc42 GTP-Binding Protein - genetics; cdc42 GTP-Binding Protein - metabolism; Child; Child, Preschool; Craniofacial Abnormalities - genetics; Craniofacial Abnormalities - metabolism; Craniofacial Abnormalities - pathology; developmental anomalies; exome sequencing; Female; functional profiling; Gene Expression; Genetic Heterogeneity; genotype-phenotype correlations; Humans; Infant; Male; microcephaly; Models, Molecular; Muscular Atrophy - genetics; Muscular Atrophy - metabolism; Muscular Atrophy - pathology; mutation spectrum; Mutation, Missense; Neurodevelopmental Disorders - genetics; Neurodevelopmental Disorders - metabolism; Neurodevelopmental Disorders - pathology; Noonan syndrome; Noonan Syndrome - genetics; Noonan Syndrome - metabolism; Noonan Syndrome - pathology; Phenotype; phenotypic heterogeneity; Protein Structure, Secondary; Severity of Illness Index; thrombocytopenia; microcephaly; mutation spectrum; exome sequencing; thrombocytopenia; Noonan syndrome; phenotypic heterogeneity; genotype-phenotype correlations; developmental anomalies; cardiac defects; functional profiling
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2017.12.015

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.