ArticleAmerican journal of human genetics2018
Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes.
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Article in American journal of human genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 101 papers, 1 of them a synthesis that pooled it.
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101citing papers in PubMed, 1 pooled it
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101 citing papers in PubMed, 1 synthesis or guideline pooled it, 181 citations in OpenAlex.
- Auditory and Language Abilities in Children with Takenouchi-Kosaki Syndrome: A Systematic Review.Genes · 2024Pooled it
- The role of Rho GTPases in facial morphogenesis.Developmental dynamics : an official publication of the American Association of Anatomists · 2026Review
- Hearing loss associated with CDC42 in mice and humans (Takenouchi-Kosaki syndrome): CDC42 and RHOQ synergistically function in cochlear hair cells.The Journal of biological chemistry · 2026Article
- Beyond GH stimulation tests: genetic heterogeneity and treatment response in children with diagnosed GH deficiency.Journal of the Endocrine Society · 2026Article
- A matter of switch: how RAC1 variants drive distinct disorders.European journal of human genetics : EJHG · 2026Article
- Distinct sub-clusters of developmental disorder-associated variants in the switch II region of RAC1.European journal of human genetics : EJHG · 2026Article
- Molecular genotype-phenotype correlation in ACTB- and ACTG1-related non-muscle actinopathies.American journal of human genetics · 2026Article
- Immune-related actinopathies at the cross-road of immunodeficiency, autoimmunity and autoinflammation.Nature reviews. Immunology · 2026Review
- Interpreting the functional impact of genetic variants: The need for context qualifiers.American journal of human genetics · 2026Review
- Case Report: Clinical phenotypes and recombinant human growth hormone therapeutic exploration for a patient with Takenouchi-Kosaki syndrome harboring theFrontiers in pediatrics · 2026Article
- PAK1 Is Involved in Epileptogenesis by Regulating the Synaptic Plasticity of Hippocampal Neurons Through LIMK.Neurochemical research · 2025Article
- Case Report: Association of Ocular Colobomas With a Novel Missense Variant in CDC42, a Member of the Rho Family of Small GTPases.Clinical genetics · 2025Article
- In Vivo Models of Cardiovascular Disease:Biomedicines · 2025Review
- KLHL23 and RhoGDI coordinate CDC42 inactivation ensuring membrane homeostasis.Nature chemical biology · 2025Article
- Transcriptional adaptation after deletion of Cdc42 in primary T cells.Journal of cell science · 2025Article
- Long-read RNA-sequencing reveals transcript-specific regulation in human-derived cortical neurons.Open biology · 2025Article
- LIMK1 variants are associated with divergent endocrinological phenotypes and altered exocytosis dynamics.iScience · 2025Article
- Lymphatic mysteries unzipped.Nature cardiovascular research · 2025Article
- PAK3 pathogenic variant associated with sleep-related hypermotor epilepsy in a family with parental mosaicism.Epilepsia open · 2025Article
- Single-cell splicing QTL analysis in pancreatic islets.Frontiers in bioinformatics · 2025Article
41 more citing papers are in PubMed but not listed here.
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Authors and funding
49 authors at 20 institutions in 5 countries.
Simone MartinelliDepartment of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.
Oliver H F KrumbachInstitute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich-Heine University, Düsseldorf 40225, Germany.
Francesca PantaleoniGenetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome 00146, Italy.
Simona CoppolaNational Center for Rare Diseases, Istituto Superiore di Sanità, Rome 00161, Italy.
Ehsan AminInstitute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich-Heine University, Düsseldorf 40225, Germany.
Luca PannoneGenetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome 00146, Italy.
Kazem NouriInstitute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich-Heine University, Düsseldorf 40225, Germany.
Luciapia FarinaNational Center for Rare Diseases, Istituto Superiore di Sanità, Rome 00161, Italy.
Radovan DvorskyInstitute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich-Heine University, Düsseldorf 40225, Germany.
Francesca LepriGenetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome 00146, Italy.
Marcel BuchholzerInstitute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich-Heine University, Düsseldorf 40225, Germany.
Raphael KonopatzkiInstitute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich-Heine University, Düsseldorf 40225, Germany.
Laurence WalshRiley Hospital for Children, Indianapolis, IN 46202, USA.
Katelyn PayneRiley Hospital for Children, Indianapolis, IN 46202, USA.
Mary Ella PierpontDepartment of Pediatrics, University of Minnesota, Minneapolis, MN 55454, USA; Children's Hospital of Minnesota, Minneapolis, MN 55454, USA.
Samantha Schrier VerganoDivision of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, VA 23507, USA.
Katherine G LangleyGeneDX, Gaithersburg, MD 20877, USA.
Douglas LarsenDepartment of Neurology, Washington University, St. Louis, MO 63130, USA.
Kelly D FarwellAmbry Genetics, Department of Clinical Genomics, Aliso Viejo, CA 92656, USA.
Sha TangAmbry Genetics, Department of Clinical Genomics, Aliso Viejo, CA 92656, USA.
Cameron MroskeAmbry Genetics, Department of Clinical Genomics, Aliso Viejo, CA 92656, USA.
Ivan GallottaInstitute of Biosciences and Bioresources, National Research Council, 80131 Naples, Italy.
Elia Di SchiaviInstitute of Biosciences and Bioresources, National Research Council, 80131 Naples, Italy.
Matteo Della MonicaGenetica Medica, Azienda Ospedaliera Universitaria Meyer, 50139 Florence, Italy.
Licia LugliStruttura Complessa di Neonatologia, Policlinico di Modena, 41124 Modena, Italy.
Cesare RossiGenetica Medica, Policlinico S.Orsola-Malpighi, 40138 Bologna, Italy.
Marco SeriDepartment of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy.
Guido CocchiDepartment of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy.
Lindsay HendersonGeneDX, Gaithersburg, MD 20877, USA.
Berivan BaskinGeneDX, Gaithersburg, MD 20877, USA.
Mariëlle AldersDepartment of Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam 1105-AZ, the Netherlands.
Roberto Mendoza-LondonoDivision 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.
Lucie DupuisDivision of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Deborah A NickersonDepartment of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
Jessica X ChongDepartment of Pediatrics, University of Washington, Seattle, WA 98195, USA.
University of Washington Center for Mendelian Genomics
Naomi MeeksChildren's Hospital Colorado, Aurora, CO 80045, USA.
Kathleen BrownChildren's Hospital Colorado, Aurora, CO 80045, USA.
Tahnee CauseyDepartment of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23284, USA.
Megan T ChoGeneDX, Gaithersburg, MD 20877, USA.
Stephanie DemuthPraxis für Humangenetik Erfurt, Erfurt 99084, Germany.
Maria Cristina DigilioGenetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome 00146, Italy.
Bruce D GelbMindich 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.
Michael J BamshadDepartment of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
Martin ZenkerInstitute of Human Genetics, University Hospital Magdeburg, Magdeburg 39120, Germany.
Mohammad Reza AhmadianInstitute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich-Heine University, Düsseldorf 40225, Germany.
Raoul C HennekamDepartment of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam 1105-AZ, the Netherlands.
Marco TartagliaGenetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome 00146, Italy. Electronic address: marco.tartaglia@opbg.net.
Ghayda M MirzaaDepartment 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.
Heinrich Heine University Düsseldorf · DEBambino Gesù Children's Hospital · ITUniversity of Washington · USAmbry Genetics (United States) · USIstituto Superiore di Sanità · ITRiley Hospital for Children · USUniversity of Bologna · ITAcademic Medical Center · NLChild Health and Development Institute · USChildren's Hospital Colorado · USChildren's Hospital of The King's Daughters · USHospital for Sick Children · CAInstitute of Biosciences and Bioresources · ITIstituti di Ricovero e Cura a Carattere Scientifico · ITMeyer Children's Hospital · ITNational Research Council · ITPoliclinico di Modena · ITPoliclinico S.Orsola-Malpighi · ITPraxis für Humangenetik · DEUniversity Hospital Magdeburg · DE
Funding
Administrative Coordinating Center: Cardiovascular Development and Pediatric Cardiac Genomics ConsortiaU01HL131003 · NHLBI · CINCINNATI CHILDRENS HOSP MED CTR · PI CNOTA, JAMES, OLLBERDING, NICHOLAS J · 2016 to 2024
$54.8MUW Center for Mendelian GenomicsU54HG006493 · NHGRI · UNIVERSITY OF WASHINGTON · PI BAMSHAD, MICHAEL JOSEPH, NICKERSON, DEBORAH A · 2012 to 2015
$20.0MUW Center for Mendelian GenomicsUM1HG006493 · NHGRI · UNIVERSITY OF WASHINGTON · PI BAMSHAD, MICHAEL JOSEPH, LEAL, SUZANNE M · 2016 to 2020
$15.3MEnhancing and expanding the CGC Strain CollectionP40OD010440 · OD · UNIVERSITY OF MINNESOTA · PI Ann E. Rougvie · 2012 to 2026
$7.5MGenetics of Hypoplastic Left Heart SyndromeUM1HL128761 · NHLBI · J. DAVID GLADSTONE INSTITUTES · PI BERNSTEIN, DANIEL, SRIVASTAVA, DEEPAK · 2015 to 2019
$2.5MThe Genomic Basis of Congenital Heart Disease and Neurodevelopmental OutcomesUM1HL098147 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI NEWBURGER, JANE W., ROBERTS, AMY E · 2015 to 2019
$2.4MGenetics of conotruncal defects and associated neurodevelopmental outcomesUM1HL098123 · NHLBI · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI GELB, BRUCE D · 2015 to 2019
$2.3MGenetics and genomics of congenital heart disease and associated neurodevelopmental abnormalitiesUM1HL098162 · NHLBI · YALE UNIVERSITY · PI BRUECKNER, MARTINA, GUPTA, ABHA RANI · 2015 to 2019
$2.2MBridging the Gap between Genomics and Clinical Outcomes in CHDUM1HL128711 · NHLBI · UNIVERSITY OF UTAH · PI TRISTANI-FIROUZI, MARTIN, YANDELL, MARK DOUGLAS · 2015 to 2019
$2.0MGenes and pathways underlying brain overgrowth and focal cortical malformationsK08NS092898 · NINDS · SEATTLE CHILDREN'S HOSPITAL · PI MIRZAA, GHAYDA · 2015 to 2019
$930kNHGRI NIH HHS U54 HG006493NHGRI NIH HHS UM1 HG006493NHLBI NIH HHS U01 HL131003NHLBI NIH HHS UM1 HL098123NHLBI NIH HHS UM1 HL098147NHLBI NIH HHS UM1 HL098162NHLBI NIH HHS UM1 HL128711NHLBI NIH HHS UM1 HL128761NIH HHS P40 OD010440NINDS NIH HHS K08 NS092898
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.
Indexed as
Genetic HeterogeneityMutation, MissenseAbnormalities, MultipleAdolescentAdultcdc42 GTP-Binding ProteinChildChild, PreschoolCraniofacial AbnormalitiesFemaleGene ExpressionHumansInfantMaleModels, MolecularMuscular Atrophycdc42 GTP-Binding ProteinCDC42 protein, humancardiac defectsdevelopmental anomaliesexome sequencingfunctional profilinggenotype-phenotype correlationsmicrocephalymutation spectrumNoonan syndromephenotypic heterogeneitythrombocytopenia
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