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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 309-320 |
| Number of pages | 12 |
| Journal | American Journal of Human Genetics |
| Volume | 102 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 1 2018 |
Bibliographical note
Funding Information:We thank the families and referring physicians for their participation in this study. We thank Dr. David Wilson (Washington University, St. Louis) for providing clinical expertise and Dr. Serenella Venanzi (Istituto Superiore di Sanità, Rome) for technical assistance. This project was supported by the National Institute of Neurological Disorders and Stroke (NINDS) (K08NS092898 to G.M.M.), the Associazione Italiana per la Ricerca sul Cancro (AIRC) (IG17583 to M.T.), Fondazione Bambino Gesù (Vite Coraggiose to M.T.), Italian Ministry of Health (RF-2011-02349938 and Ricerca Corrente 2017 to M.T.), E-Rare (NSEuroNet to M.Z., M.R.A., and M.T.), International Research Training Group 1902 Intra- and Interorgan Communication of the Cardiovascular System (IRTG 1902 to E.A., M.B., and M.R.A.), and Medical Faculty of the Heinrich-Heine University Duesseldorf (9772617 to K.N., O.H.F.K., R.K., and M.R.A.). Exome sequencing was performed at the University of Washington Center for Mendelian Genomics (UW-CMG) and was funded by the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute grant HG006493 (to D.A.N. and M.J.B.). This work was also supported by grants U01HL131003, UM1HL098147, UM1HL098123, UM1HL128761, UM1HL128711, and UM1HL098162 in support of the Pediatric Cardiac Genomics Consortium from the National Heart, Lung, and Blood Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. C. elegans strains were provided by the Caenorhabditis Genetics Center, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). We also thank WormBase, the contributors to MyGene2, and the University of Washington Center for Mendelian Genomics for use of data.
Funding Information:
We thank the families and referring physicians for their participation in this study. We thank Dr. David Wilson (Washington University, St. Louis) for providing clinical expertise and Dr. Serenella Venanzi (Istituto Superiore di Sanità, Rome) for technical assistance. This project was supported by the National Institute of Neurological Disorders and Stroke (NINDS) ( K08NS092898 to G.M.M.), the Associazione Italiana per la Ricerca sul Cancro (AIRC) ( IG17583 to M.T.), Fondazione Bambino Gesù (Vite Coraggiose to M.T.), Italian Ministry of Health ( RF-2011-02349938 and Ricerca Corrente 2017 to M.T.), E-Rare ( NSEuroNet to M.Z., M.R.A., and M.T.), International Research Training Group 1902 Intra- and Interorgan Communication of the Cardiovascular System ( IRTG 1902 to E.A., M.B., and M.R.A.), and Medical Faculty of the Heinrich-Heine University Duesseldorf ( 9772617 to K.N., O.H.F.K., R.K., and M.R.A.). Exome sequencing was performed at the University of Washington Center for Mendelian Genomics (UW-CMG) and was funded by the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute grant HG006493 (to D.A.N. and M.J.B.). This work was also supported by grants U01HL131003 , UM1HL098147 , UM1HL098123 , UM1HL128761 , UM1HL128711 , and UM1HL098162 in support of the Pediatric Cardiac Genomics Consortium from the National Heart, Lung, and Blood Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development . C. elegans strains were provided by the Caenorhabditis Genetics Center, which is funded by NIH Office of Research Infrastructure Programs ( P40 OD010440 ). We also thank WormBase, the contributors to MyGene2, and the University of Washington Center for Mendelian Genomics for use of data.
Publisher Copyright:
© 2017 American Society of Human Genetics
Keywords
- Noonan syndrome
- cardiac defects
- developmental anomalies
- exome sequencing
- functional profiling
- genotype-phenotype correlations
- microcephaly
- mutation spectrum
- phenotypic heterogeneity
- thrombocytopenia