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Cognitive and behavioural genetics
Original article
Mutations specific to the Rac-GEF domain of TRIO cause intellectual disability and microcephaly
  1. Reuben J Pengelly1,
  2. Stephanie Greville-Heygate2,
  3. Susanne Schmidt3,
  4. Eleanor G Seaby1,
  5. M Reza Jabalameli1,
  6. Sarju G Mehta4,
  7. Michael J Parker5,
  8. David Goudie6,
  9. Christine Fagotto-Kaufmann3,
  10. Catherine Mercer2,
  11. the DDD Study7,
  12. Anne Debant3,
  13. Sarah Ennis1,
  14. Diana Baralle2
  1. 1Department of Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK
  2. 2Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK
  3. 3Centre de Recherche en Biologie Cellulaire de Montpellier, Centre National de la Recherche Scientifique, Université de Montpellier, Montpellier, Cédex, France
  4. 4Department of Clinical Genetics, Cambridge University Hospital Trust, Cambridge, UK
  5. 5Sheffield Clinical Genetics Service, Sheffield Children's Hospital NHS Foundation Trust, OPD2, Northern General Hospital, Sheffield, UK
  6. 6Department of Clinical Genetics, Ninewells Hospital, Dundee, UK
  7. 7Wellcome Trust Sanger Institute, Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
  1. Correspondence to
    Dr Diana Baralle, Human Development and Health, Duthie Building, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK; d.baralle{at}soton.ac.uk

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 includes TRIO, 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 in TRIO that segregated autosomal dominantly. By scrutinising data from DDD, we further identified three unrelated children with a similar phenotype who harboured de novo missense mutations in TRIO. 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 in TRIO. Additionally, we identify pathogenic de novo missense mutations in TRIO associated 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.

  • Microcephaly
  • TRIO
  • Dbl
  • Rho GTPase
  • Rac1

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/jmedgenet-2016-103942

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    Footnotes

    • RJP, SG-H, SS, EGS, SE and DB contributed equally.

    • Contributors DB conceived the project and coordinated cases and functional work, contributed to the writing, examined and phenotyped the cases, edited the manuscript and contributed funding for sequencing. SE, RJP, MRJ and EGS undertook WES of the large family and discovered the first TRIO mutations. They jointly wrote and edited drafts. SGM, MJP and DG all contributed patients and their phenotypes through the DDD Study who did the WES of these three cases. SG-H and CM are clinicians involved in the care and phenotype of the large dominant family. CF-K, SS and AD performed the functional assays.

    • Funding RJP is supported by the University of Southampton. The functional work was supported by an Agence Nationale de la Recherche grant (ANR-14-CE11-0025-01) awarded to AD.

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC).

    • Provenance and peer review Not commissioned; externally peer reviewed.