Extending the phenotypes associated with TRIO gene variants in a cohort of 25 patients and review of the literature

Gabriella Gazdagh^{1

2}, David Hunt¹, Anna Maria Cueto Gonzalez³, Monserrat Pons Rodriguez⁴, Ayeshah Chaudhry^{5

6}, Marcos Madruga⁷, Fleur Vansenne⁸, Deborah Shears⁹, Aurore Curie¹⁰, Eva-Lena Stattin¹¹, Britt-Marie Anderlid¹², Slavica Trajkova¹³, Elena Sukarova Angelovska¹⁴, Catherine McWilliam¹⁵, Philip R Wyatt¹⁶, Mary O'Driscoll¹⁷, Giles Atton¹, Anke K Bergman¹⁸, Pia Zacher^{19

20}, Leena D Mewasingh²¹, Antonio Gonzalez-Meneses López²², Olga Alonso-Luengo²³, Htoo A Wai², Ottilie Rohde², Pauline Boiroux²⁴, Anne Debant²⁴, Susanne Schmidt²⁴, Diana Baralle²

Affiliations

¹ Wessex Clinical Genetics Service, Princess Anne Hospital, University Hospital Southampton NHS Trust, Southampton, UK.
² Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
³ Department of Clinical and Molecular Genetics, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
⁴ Hospital Universitari Son Espases, 07120, Palma, Illes Balears, Spain.
⁵ Department of Laboratory Medicine and Genetics, Trillium Health Partners, Mississauga, Ontario, Canada.
⁶ Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.
⁷ Hospital Viamed Santa Ángela De la Cruz, Sevilla, 41014, Spain.
⁸ Department of Clinical Genetics, University Medical Center Groningen, 9713 GZ, Groningen, The Netherlands.
⁹ Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
¹⁰ Reference Center for Intellectual Disability From Rrare Causes, Department of Child Neurology, Woman Mother and Child Hospital, Hospices Civils de Lyon, Lyon Neuroscience Research Centre, CNRS UMR5292, INSERM U1028, Université de Lyon, Bron, France.
¹¹ Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
¹² Department of Molecular Medicine and Surgery, Karolinska Institute and Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
¹³ Department of Medical Sciences, Medical Genetics and Rare diseases, University of Turin, Turin, Italy.
¹⁴ Department of Endocronology and Genetics, University Clinic for Children's Diseases, Medical Faculty, University Sv. Kiril i Metodij, Skopje, Republic of Macedonia.
¹⁵ NHS Tayside, Ninewells Hospital, Dundee, UK.
¹⁶ Department of Obstetrics and Gynecology, York Central Hospital, Toronto, Canada.
¹⁷ West Midlands Regional Genetics Service, Birmingham, UK.
¹⁸ Hannover Medical School, Institute of Human Genetics, Hannover, Germany.
¹⁹ Epilepsy Center Kleinwachau, Radeberg, Germany.
²⁰ Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
²¹ Department of Paediatric Neurology, Imperial College Healthcare NHS Trust, London, UK.
²² Unidad de Dismorfologia, Unidad de Gestión Clínica de Pediatría, Hospital Universitario Virgen del Rocio, Sevilla, Pediatric department, University of Seville, Spain.
²³ Sección de Neurología Pediátrica, Unidad de Gestión Clínica de Pediatría. Hospital Universitario Virgen del Rocio, Sevilla, Pediatric department, University of Seville, Spain.
²⁴ Centre de Recherche en Biologie Cellulaire de Montpellier (CRBM), University of Montpellier CNRS, Montpellier, France.

PMID: 36987741
DOI: 10.1002/ajmg.a.63194

Review

Extending the phenotypes associated with TRIO gene variants in a cohort of 25 patients and review of the literature

Gabriella Gazdagh et al. Am J Med Genet A. 2023 Jul.

. 2023 Jul;191(7):1722-1740.

doi: 10.1002/ajmg.a.63194. Epub 2023 Mar 29.

Authors

Affiliations

¹ Wessex Clinical Genetics Service, Princess Anne Hospital, University Hospital Southampton NHS Trust, Southampton, UK.
² Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
³ Department of Clinical and Molecular Genetics, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
⁴ Hospital Universitari Son Espases, 07120, Palma, Illes Balears, Spain.
⁵ Department of Laboratory Medicine and Genetics, Trillium Health Partners, Mississauga, Ontario, Canada.
⁶ Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.
⁷ Hospital Viamed Santa Ángela De la Cruz, Sevilla, 41014, Spain.
⁸ Department of Clinical Genetics, University Medical Center Groningen, 9713 GZ, Groningen, The Netherlands.
⁹ Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
¹⁰ Reference Center for Intellectual Disability From Rrare Causes, Department of Child Neurology, Woman Mother and Child Hospital, Hospices Civils de Lyon, Lyon Neuroscience Research Centre, CNRS UMR5292, INSERM U1028, Université de Lyon, Bron, France.
¹¹ Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
¹² Department of Molecular Medicine and Surgery, Karolinska Institute and Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
¹³ Department of Medical Sciences, Medical Genetics and Rare diseases, University of Turin, Turin, Italy.
¹⁴ Department of Endocronology and Genetics, University Clinic for Children's Diseases, Medical Faculty, University Sv. Kiril i Metodij, Skopje, Republic of Macedonia.
¹⁵ NHS Tayside, Ninewells Hospital, Dundee, UK.
¹⁶ Department of Obstetrics and Gynecology, York Central Hospital, Toronto, Canada.
¹⁷ West Midlands Regional Genetics Service, Birmingham, UK.
¹⁸ Hannover Medical School, Institute of Human Genetics, Hannover, Germany.
¹⁹ Epilepsy Center Kleinwachau, Radeberg, Germany.
²⁰ Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
²¹ Department of Paediatric Neurology, Imperial College Healthcare NHS Trust, London, UK.
²² Unidad de Dismorfologia, Unidad de Gestión Clínica de Pediatría, Hospital Universitario Virgen del Rocio, Sevilla, Pediatric department, University of Seville, Spain.
²³ Sección de Neurología Pediátrica, Unidad de Gestión Clínica de Pediatría. Hospital Universitario Virgen del Rocio, Sevilla, Pediatric department, University of Seville, Spain.
²⁴ Centre de Recherche en Biologie Cellulaire de Montpellier (CRBM), University of Montpellier CNRS, Montpellier, France.

PMID: 36987741
DOI: 10.1002/ajmg.a.63194

Abstract

The TRIO gene encodes a rho guanine exchange factor, the function of which is to exchange GDP to GTP, and hence to activate Rho GTPases, and has been described to impact neurodevelopment. Specific genotype-to-phenotype correlations have been established previously describing striking differentiating features seen in variants located in specific domains of the TRIO gene that are associated with opposite effects on RAC1 activity. Currently, 32 cases with a TRIO gene alteration have been published in the medical literature. Here, we report an additional 25, previously unreported individuals who possess heterozygous TRIO variants and we review the literature. In addition, functional studies were performed on the c.4394A > G (N1465S) and c.6244-2A > G TRIO variants to provide evidence for their pathogenicity. Variants reported by the current study include missense variants, truncating nonsense variants, and an intragenic deletion. Clinical features were previously described and included developmental delay, learning difficulties, microcephaly, macrocephaly, seizures, behavioral issues (aggression, stereotypies), skeletal problems including short, tapering fingers and scoliosis, dental problems (overcrowding/delayed eruption), and variable facial features. Here, we report clinical features that have not been described previously, including specific structural brain malformations such as abnormalities of the corpus callosum and ventriculomegaly, additional psychological and dental issues along with a more recognizable facial gestalt linked to the specific domains of the TRIO gene and the effect of the variant upon the function of the encoded protein. This current study further strengthens the genotype-to-phenotype correlation that was previously established and extends the range of phenotypes to include structural brain abnormalities, additional skeletal, dental, and psychiatric issues.

Keywords: GEFD; TRIO gene; macrocephaly; microcephaly; phenotype; spectrin.

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References

REFERENCES

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Extending the phenotypes associated with TRIO gene variants in a cohort of 25 patients and review of the literature

Affiliations

Extending the phenotypes associated with TRIO gene variants in a cohort of 25 patients and review of the literature

Authors

Affiliations

Abstract

References

REFERENCES

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources