De novo missense variants in RAC3 cause a novel neurodevelopmental syndrome

Genet Med. 2019 Apr;21(4):1021-1026. doi: 10.1038/s41436-018-0323-y.

Gregory Costain ¹, Bert Callewaert ², Heinz Gabriel ³, Tiong Y Tan ⁴, Susan Walker ⁵ ⁶, John Christodoulou ⁴ ⁷, Tamas Lazar ⁸, Björn Menten ², Julia Orkin ⁹ ¹⁰ ¹¹, Simon Sadedin ⁴, Meaghan Snell ¹² ¹³, Arnaud Vanlander ¹⁴, Sarah Vergult ², Susan M White ⁴, Stephen W Scherer ⁵ ⁶ ¹⁵, Robin Z Hayeems ¹¹ ¹³, Susan Blaser ¹⁶, Shoshana J Wodak ⁸, David Chitayat ¹² ¹⁷, Christian R Marshall ¹⁸ ¹⁹ ²⁰ ²¹, M Stephen Meyn ²² ²³ ²⁴ ²⁵ ²⁶

Affiliations

1 Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada. [email protected].
2 Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
3 Center for Genomics and Transcriptomics, Eberhard Karls University of Tübingen, Tübingen, Germany.
4 Victorian Clinical Genetics Services, Murdoch Children's Research Institute, & Department of Paediatrics, University of Melbourne, Melbourne, Australia.
5 The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada.
6 Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
7 Neurodevelopmental Genomics Research Group, Murdoch Children's Research Institute, Melbourne, Australia.
8 VIB-VUB Structural Biology Research Center, Brussels, Belgium.
9 Department of Paediatrics, University of Toronto, Toronto, ON, Canada.
10 Division of Paediatric Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
11 Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, ON, Canada.
12 Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada.
13 Centre for Genetic Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
14 Department of Pediatrics, Ghent University, Ghent, Belgium.
15 Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
16 Department of Diagnostic Imaging, The Hospital for Sick Children, Toronto, ON, Canada.
17 The Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
18 The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada. [email protected].
19 Centre for Genetic Medicine, The Hospital for Sick Children, Toronto, ON, Canada. [email protected].
20 Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada. [email protected].
21 Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. [email protected].
22 Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada. [email protected].
23 Department of Paediatrics, University of Toronto, Toronto, ON, Canada. [email protected].
24 Centre for Genetic Medicine, The Hospital for Sick Children, Toronto, ON, Canada. [email protected].
25 Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. [email protected].
26 Center for Human Genomics and Precision Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States. [email protected].

PMID: 30293988 DOI: 10.1038/s41436-018-0323-y

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

GTPase; Rho signaling; exome; genome; neurodevelopment.

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