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.
journal_name
Am J Hum Genetjournal_title
American journal of human geneticsauthors
Martinelli S,Krumbach OHF,Pantaleoni F,Coppola S,Amin E,Pannone L,Nouri K,Farina L,Dvorsky R,Lepri F,Buchholzer M,Konopatzki R,Walsh L,Payne K,Pierpont ME,Vergano SS,Langley KG,Larsen D,Farwell KD,Tang S,Mroske Cdoi
10.1016/j.ajhg.2017.12.015subject
Has Abstractpub_date
2018-02-01 00:00:00pages
309-320issue
2eissn
0002-9297issn
1537-6605pii
S0002-9297(17)30504-9journal_volume
102pub_type
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