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Am J Hum Genet. 2018 Feb 1;102(2):309-320. doi: 10.1016/j.ajhg.2017.12.015. Epub 2018 Jan 25.

Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes.

Author information

1
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.
2
Institute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich-Heine University, Düsseldorf 40225, Germany.
3
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome 00146, Italy.
4
National Center for Rare Diseases, Istituto Superiore di Sanità, Rome 00161, Italy.
5
Riley Hospital for Children, Indianapolis, IN 46202, USA.
6
Department of Pediatrics, University of Minnesota, Minneapolis, MN 55454, USA; Children's Hospital of Minnesota, Minneapolis, MN 55454, USA.
7
Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, VA 23507, USA.
8
GeneDX, Gaithersburg, MD 20877, USA.
9
Department of Neurology, Washington University, St. Louis, MO 63130, USA.
10
Ambry Genetics, Department of Clinical Genomics, Aliso Viejo, CA 92656, USA.
11
Institute of Biosciences and Bioresources, National Research Council, 80131 Naples, Italy.
12
Genetica Medica, Azienda Ospedaliera Universitaria Meyer, 50139 Florence, Italy.
13
Struttura Complessa di Neonatologia, Policlinico di Modena, 41124 Modena, Italy.
14
Genetica Medica, Policlinico S.Orsola-Malpighi, 40138 Bologna, Italy.
15
Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy.
16
Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam 1105-AZ, the Netherlands.
17
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
18
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
19
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
20
Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
21
Children's Hospital Colorado, Aurora, CO 80045, USA.
22
Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23284, USA.
23
Praxis für Humangenetik Erfurt, Erfurt 99084, Germany.
24
Mindich Child Health and Development Institute and Departments of Pediatrics, and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
25
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
26
Institute of Human Genetics, University Hospital Magdeburg, Magdeburg 39120, Germany.
27
Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam 1105-AZ, the Netherlands.
28
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome 00146, Italy. Electronic address: marco.tartaglia@opbg.net.
29
Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA. Electronic address: gmirzaa@u.washington.edu.

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.

KEYWORDS:

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

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