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Mutations specific to the Rac-GEF domain of TRIO causes intellectual disability and microcephaly

Mutations specific to the Rac-GEF domain of TRIO causes intellectual disability and microcephaly
Mutations specific to the Rac-GEF domain of TRIO causes intellectual disability and microcephaly
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.
0022-2593
735-742
Pengelly, Reuben
af97c0c1-b568-415c-9f59-1823b65be76d
Greville-Heygate, Stephanie
b0f6f01f-f3ce-4e23-af30-fab3b51717dc
Schmidt, Susanne
03033526-316a-441b-9d86-2f0e9dd2e034
Seaby, Eleanor G
f004c141-6123-4b7d-8220-ebfff556867b
Jabalameli, M Reza
d533e702-7a6b-4f2d-8947-352ea1dd769b
Mehta, Sarju G
0bfdbed3-b047-4e84-8490-a5c972585ffc
Parker, Michael J
9a223cab-0ee5-417e-93e4-199f139f3ffc
Goudie, David
39308a71-f42b-4e4f-8e2a-05053b6a84fc
Fagotto-Kaufmann, Christine
99a06044-bc60-4455-b111-5ca9c18604f1
Mercer, Catherine
14ff7942-6f8f-4031-b8f6-bdc2f1465524
Debant, Anne
1c73311f-e345-448b-a1e1-b542e7c4647e
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Baralle, Diana
faac16e5-7928-4801-9811-8b3a9ea4bb91
Pengelly, Reuben
af97c0c1-b568-415c-9f59-1823b65be76d
Greville-Heygate, Stephanie
b0f6f01f-f3ce-4e23-af30-fab3b51717dc
Schmidt, Susanne
03033526-316a-441b-9d86-2f0e9dd2e034
Seaby, Eleanor G
f004c141-6123-4b7d-8220-ebfff556867b
Jabalameli, M Reza
d533e702-7a6b-4f2d-8947-352ea1dd769b
Mehta, Sarju G
0bfdbed3-b047-4e84-8490-a5c972585ffc
Parker, Michael J
9a223cab-0ee5-417e-93e4-199f139f3ffc
Goudie, David
39308a71-f42b-4e4f-8e2a-05053b6a84fc
Fagotto-Kaufmann, Christine
99a06044-bc60-4455-b111-5ca9c18604f1
Mercer, Catherine
14ff7942-6f8f-4031-b8f6-bdc2f1465524
Debant, Anne
1c73311f-e345-448b-a1e1-b542e7c4647e
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Baralle, Diana
faac16e5-7928-4801-9811-8b3a9ea4bb91

Pengelly, Reuben, Greville-Heygate, Stephanie, Schmidt, Susanne, Seaby, Eleanor G, Jabalameli, M Reza, Mehta, Sarju G, Parker, Michael J, Goudie, David, Fagotto-Kaufmann, Christine, Mercer, Catherine, Debant, Anne, Ennis, Sarah and Baralle, Diana (2016) Mutations specific to the Rac-GEF domain of TRIO causes intellectual disability and microcephaly. Journal of Medical Genetics, 53 (11), 735-742. (doi:10.1136/jmedgenet-2016-103942).

Record type: Article

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.

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Accepted/In Press date: 7 July 2016
e-pub ahead of print date: 14 July 2016
Published date: November 2016
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 397881
URI: http://eprints.soton.ac.uk/id/eprint/397881
ISSN: 0022-2593
PURE UUID: db280a87-2a8d-4b4d-a711-29d2942b4d62
ORCID for Reuben Pengelly: ORCID iD orcid.org/0000-0001-7022-645X
ORCID for M Reza Jabalameli: ORCID iD orcid.org/0000-0002-7762-0529
ORCID for Sarah Ennis: ORCID iD orcid.org/0000-0003-2648-0869
ORCID for Diana Baralle: ORCID iD orcid.org/0000-0003-3217-4833

Catalogue record

Date deposited: 08 Jul 2016 12:50
Last modified: 18 Feb 2021 17:22

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Contributors

Author: Reuben Pengelly ORCID iD
Author: Stephanie Greville-Heygate
Author: Susanne Schmidt
Author: Eleanor G Seaby
Author: M Reza Jabalameli ORCID iD
Author: Sarju G Mehta
Author: Michael J Parker
Author: David Goudie
Author: Christine Fagotto-Kaufmann
Author: Catherine Mercer
Author: Anne Debant
Author: Sarah Ennis ORCID iD
Author: Diana Baralle ORCID iD

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