Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes

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 tha...

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Bibliographic Details
Published in:American journal of human genetics 2018-02, Vol.102 (2), p.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: Article
Language:English
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
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Summary: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.
ISSN:0002-9297
1537-6605
DOI:10.1016/j.ajhg.2017.12.015