title: Mutations specific to the Rac-GEF domain ofTRIOcause intellectual disability and microcephaly.
abstract: BACKGROUND
  Neurodevelopmental disorders have challenged clinical genetics for decades, with over 700 genes implicated and many whose function remains unknown. The application of whole-exome sequencing is proving pivotal in closing the genotype/phenotype gap through the discovery of new genes and variants that help to unravel the pathogenic mechanisms driving neuropathogenesis. One such discovery includesTRIO, a gene recently implicated in neurodevelopmental delay. Trio is a Dbl family guanine nucleotide exchange factor (GEF) and a major regulator of neuronal development, controlling actin cytoskeleton dynamics by activating the GTPase Rac1.
  
  
  METHODS
  Whole-exome sequencing was undertaken on a family presenting with global developmental delay, microcephaly and mild dysmorphism. Father/daughter exome analysis was performed, followed by confirmatory Sanger sequencing and segregation analysis on four individuals. Three further patients were recruited through the deciphering developmental disorders (DDD) study. Functional studies were undertaken using patient-specific Trio protein mutations.
  
  
  RESULTS
  We identified a frameshift deletion inTRIOthat segregated autosomal dominantly. By scrutinising data from DDD, we further identified three unrelated children with a similar phenotype who harboured de novo missense mutations inTRIO. Biochemical studies demonstrated that in three out of four families, the Trio mutations led to a markedly reduced Rac1 activation.
  
  
  CONCLUSIONS
  We describe an inherited global developmental delay phenotype associated with a frameshift deletion inTRIO. Additionally, we identify pathogenic de novo missense mutations inTRIOassociated with the same consistent phenotype, intellectual disability, microcephaly and dysmorphism with striking digital features. We further functionally validate the importance of the GEF domain in Trio protein function. Our study demonstrates how genomic technologies are yet again proving prolific in diagnosing and advancing the understanding of neurodevelopmental disorders.
authors.affiliation: Department of Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Reuben J
authors.initials: RJ
authors.lastname: Pengelly
authors.affiliation: Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Greville-Heygate
authors.affiliation: Centre de Recherche en Biologie Cellulaire de Montpellier, Centre National de la Recherche Scientifique, Université de Montpellier, Montpellier, Cédex, France.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Department of Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Eleanor G
authors.initials: EG
authors.lastname: Seaby
authors.affiliation: Department of Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: M Reza
authors.initials: MR
authors.lastname: Jabalameli
authors.affiliation: Department of Clinical Genetics, Cambridge University Hospital Trust, Cambridge, UK.
authors.forename: Sarju G
authors.initials: SG
authors.lastname: Mehta
authors.affiliation: Sheffield Clinical Genetics Service, Sheffield Children's Hospital NHS Foundation Trust, OPD2, Northern General Hospital, Sheffield, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Parker
authors.affiliation: Department of Clinical Genetics, Ninewells Hospital, Dundee, UK.
authors.forename: David
authors.initials: D
authors.lastname: Goudie
authors.affiliation: Centre de Recherche en Biologie Cellulaire de Montpellier, Centre National de la Recherche Scientifique, Université de Montpellier, Montpellier, Cédex, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Fagotto-Kaufmann
authors.affiliation: Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Mercer
authors.affiliation: Centre de Recherche en Biologie Cellulaire de Montpellier, Centre National de la Recherche Scientifique, Université de Montpellier, Montpellier, Cédex, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Debant
authors.affiliation: Department of Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ennis
authors.affiliation: Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Baralle
keywords: Dbl; Microcephaly; Rac1; Rho GTPase; TRIO