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De novo missense variants in RAC3 cause a novel neurodevelopmental syndrome

(2019) GENETICS IN MEDICINE. 21(4). p.1021-1026
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Abstract
Purpose: RAC3 is an underexamined member of the Rho GTPase gene family that is expressed in the developing brain and linked to key cellular functions. De novo missense variants in the homolog RAC1 were recently associated with developmental disorders. In the RAC subfamily, transforming missense changes at certain shared residues have been observed in human cancers and previously characterized in experimental studies. The purpose of this study was to determine whether constitutional dysregulation of RAC3 is associated with human disease. Methods: We discovered a RAC3 variant in the index case using genome sequencing, and searched for additional variants using international data-sharing initiatives. Functional effects of the variants were assessed using a multifaceted approach generalizable to most clinical laboratory settings. Results: We rapidly identified five individuals with de novo monoallelic missense variants in RAC3, including one recurrent change. Every participant had severe intellectual disability and brain malformations. In silico protein modeling, and prior in vivo and in situ experiments, supported a transforming effect for each of the three different RAC3 variants. All variants were observed in databases of somatic variation in cancer. Conclusions: Missense variants in RAC3 cause a novel brain disorder, likely through a mechanism of constitutive protein activation.
Keywords
exome, genome, neurodevelopment, Rho signaling, GTPase, NUCLEOTIDE EXCHANGE FACTOR, MUTATIONS, GTPASES, SWITCH

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Citation

Please use this url to cite or link to this publication:

MLA
Costain, Gregory, et al. “De Novo Missense Variants in RAC3 Cause a Novel Neurodevelopmental Syndrome.” GENETICS IN MEDICINE, vol. 21, no. 4, 2019, pp. 1021–26.
APA
Costain, G., Callewaert, B., Gabriel, H., Tan, T. Y., Walker, S., Christodoulou, J., … Meyn, M. S. (2019). De novo missense variants in RAC3 cause a novel neurodevelopmental syndrome. GENETICS IN MEDICINE, 21(4), 1021–1026.
Chicago author-date
Costain, Gregory, Bert Callewaert, Heinz Gabriel, Tiong Y Tan, Susan Walker, John Christodoulou, Tamas Lazar, et al. 2019. “De Novo Missense Variants in RAC3 Cause a Novel Neurodevelopmental Syndrome.” GENETICS IN MEDICINE 21 (4): 1021–26.
Chicago author-date (all authors)
Costain, Gregory, Bert Callewaert, Heinz Gabriel, Tiong Y Tan, Susan Walker, John Christodoulou, Tamas Lazar, Björn Menten, Julia Orkin, Simon Sadedin, Meaghan Snell, Arnaud Vanlander, Sarah Vergult, Susan M White, Stephen W Scherer, Robin Z Hayeems, Susan Blaser, Shoshana J Wodak, David Chitayat, Christian R Marshall, and M Stephen Meyn. 2019. “De Novo Missense Variants in RAC3 Cause a Novel Neurodevelopmental Syndrome.” GENETICS IN MEDICINE 21 (4): 1021–1026.
Vancouver
1.
Costain G, Callewaert B, Gabriel H, Tan TY, Walker S, Christodoulou J, et al. De novo missense variants in RAC3 cause a novel neurodevelopmental syndrome. GENETICS IN MEDICINE. 2019;21(4):1021–6.
IEEE
[1]
G. Costain et al., “De novo missense variants in RAC3 cause a novel neurodevelopmental syndrome,” GENETICS IN MEDICINE, vol. 21, no. 4, pp. 1021–1026, 2019.
@article{8583612,
  abstract     = {Purpose: RAC3 is an underexamined member of the Rho GTPase gene family that is expressed in the developing brain and linked to key cellular functions. De novo missense variants in the homolog RAC1 were recently associated with developmental disorders. In the RAC subfamily, transforming missense changes at certain shared residues have been observed in human cancers and previously characterized in experimental studies. The purpose of this study was to determine whether constitutional dysregulation of RAC3 is associated with human disease. 
Methods: We discovered a RAC3 variant in the index case using genome sequencing, and searched for additional variants using international data-sharing initiatives. Functional effects of the variants were assessed using a multifaceted approach generalizable to most clinical laboratory settings. 
Results: We rapidly identified five individuals with de novo monoallelic missense variants in RAC3, including one recurrent change. Every participant had severe intellectual disability and brain malformations. In silico protein modeling, and prior in vivo and in situ experiments, supported a transforming effect for each of the three different RAC3 variants. All variants were observed in databases of somatic variation in cancer. 
Conclusions: Missense variants in RAC3 cause a novel brain disorder, likely through a mechanism of constitutive protein activation.},
  author       = {Costain, Gregory and Callewaert, Bert and Gabriel, Heinz and Tan, Tiong Y and Walker, Susan and Christodoulou, John and Lazar, Tamas and Menten, Björn and Orkin, Julia and Sadedin, Simon and Snell, Meaghan and Vanlander, Arnaud and Vergult, Sarah and White, Susan M and Scherer, Stephen W and Hayeems, Robin Z and Blaser, Susan and Wodak, Shoshana J and Chitayat, David and Marshall, Christian R and Meyn, M Stephen},
  issn         = {1098-3600},
  journal      = {GENETICS IN MEDICINE},
  keywords     = {exome,genome,neurodevelopment,Rho signaling,GTPase,NUCLEOTIDE EXCHANGE FACTOR,MUTATIONS,GTPASES,SWITCH},
  language     = {eng},
  number       = {4},
  pages        = {1021--1026},
  title        = {De novo missense variants in RAC3 cause a novel neurodevelopmental syndrome},
  url          = {http://dx.doi.org/10.1038/s41436-018-0323-y},
  volume       = {21},
  year         = {2019},
}

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