{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:17:02Z","timestamp":1792793822186,"version":"4.5.0"},"reference-count":20,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2023,3,29]],"date-time":"2023-03-29T00:00:00Z","timestamp":1680048000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR\u20102019 TRIOTISM"],"award-info":[{"award-number":["ANR\u20102019 TRIOTISM"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health and Care Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health and Care Research","doi-asserted-by":"publisher","award":["RP\u20102016\u201007\u2010011"],"award-info":[{"award-number":["RP\u20102016\u201007\u2010011"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2023,7]]},"abstract":"Abstract<\/jats:title>The TRIO<\/jats:italic> 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\u2010to\u2010phenotype correlations have been established previously describing striking differentiating features seen in variants located in specific domains of the TRIO<\/jats:italic> gene that are associated with opposite effects on RAC1 activity. Currently, 32 cases with a TRIO<\/jats:italic> gene alteration have been published in the medical literature. Here, we report an additional 25, previously unreported individuals who possess heterozygous TRIO<\/jats:italic> variants and we review the literature. In addition, functional studies were performed on the c.4394A\u2009>\u2009G (N1465S) and c.6244\u20102A\u2009>\u2009G TRIO<\/jats:italic> 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<\/jats:italic> gene and the effect of the variant upon the function of the encoded protein. This current study further strengthens the genotype\u2010to\u2010phenotype correlation that was previously established and extends the range of phenotypes to include structural brain abnormalities, additional skeletal, dental, and psychiatric issues.<\/jats:p>","DOI":"10.1002\/ajmg.a.63194","type":"journal-article","created":{"date-parts":[[2023,3,29]],"date-time":"2023-03-29T09:20:56Z","timestamp":1680081656000},"page":"1722-1740","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Extending the phenotypes associated with TRIO<\/i><\/scp> gene variants in a cohort of 25 patients and review of the literature"],"prefix":"10.1002","volume":"191","author":[{"given":"Gabriella","family":"Gazdagh","sequence":"first","affiliation":[{"name":"Wessex Clinical Genetics Service, Princess Anne Hospital University Hospital Southampton NHS Trust Southampton UK"},{"name":"Human Development and Health, Faculty of Medicine University of Southampton Southampton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Hunt","sequence":"additional","affiliation":[{"name":"Wessex Clinical Genetics Service, Princess Anne Hospital University Hospital Southampton NHS Trust Southampton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria Cueto","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Genetics Vall d'Hebron Barcelona Hospital Campus Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monserrat Pons","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Hospital Universitari Son Espases 07120 Palma, Illes Balears Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayeshah","family":"Chaudhry","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Genetics Trillium Health Partners Mississauga Ontario Canada"},{"name":"Department of Laboratory Medicine and Pathobiology University of Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcos","family":"Madruga","sequence":"additional","affiliation":[{"name":"Hospital Viamed Santa \u00c1ngela De la Cruz Sevilla 41014 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fleur","family":"Vansenne","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics University Medical Center Groningen 9713 GZ Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Shears","sequence":"additional","affiliation":[{"name":"Oxford Centre for Genomic Medicine Oxford University Hospitals NHS Foundation Trust Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurore","family":"Curie","sequence":"additional","affiliation":[{"name":"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 Universit\u00e9 de Lyon Bron France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva\u2010Lena","family":"Stattin","sequence":"additional","affiliation":[{"name":"Department of Immunology, Genetics and Pathology Uppsala University Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Britt\u2010Marie","family":"Anderlid","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Surgery, Karolinska Institute and Clinical Genetics Karolinska University Hospital Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Slavica","family":"Trajkova","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Medical Genetics and Rare diseases University of Turin Turin Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena Sukarova","family":"Angelovska","sequence":"additional","affiliation":[{"name":"Department of Endocronology and Genetics, University Clinic for Children's Diseases, Medical Faculty University Sv. Kiril i Metodij Skopje Republic of Macedonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"McWilliam","sequence":"additional","affiliation":[{"name":"NHS Tayside Ninewells Hospital Dundee UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip R.","family":"Wyatt","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology York Central Hospital Toronto Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"O'Driscoll","sequence":"additional","affiliation":[{"name":"West Midlands Regional Genetics Service Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giles","family":"Atton","sequence":"additional","affiliation":[{"name":"Wessex Clinical Genetics Service, Princess Anne Hospital University Hospital Southampton NHS Trust Southampton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anke K.","family":"Bergman","sequence":"additional","affiliation":[{"name":"Hannover Medical School Institute of Human Genetics Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pia","family":"Zacher","sequence":"additional","affiliation":[{"name":"Epilepsy Center Kleinwachau Radeberg Germany"},{"name":"Institute of Human Genetics University of Leipzig Medical Center Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leena D.","family":"Mewasingh","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neurology Imperial College Healthcare NHS Trust London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio Gonzalez\u2010Meneses","family":"L\u00f3pez","sequence":"additional","affiliation":[{"name":"Unidad de Dismorfologia, Unidad de Gesti\u00f3n Cl\u00ednica de Pediatr\u00eda, Hospital Universitario Virgen del Rocio, Sevilla, Pediatric department University of Seville Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Alonso\u2010Luengo","sequence":"additional","affiliation":[{"name":"Secci\u00f3n de Neurolog\u00eda Pedi\u00e1trica, Unidad de Gesti\u00f3n Cl\u00ednica de Pediatr\u00eda. 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