{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T03:51:14Z","timestamp":1777348274932,"version":"3.51.4"},"reference-count":20,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2024,3,22]],"date-time":"2024-03-22T00:00:00Z","timestamp":1711065600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Pathogenic variants in <jats:italic>TRIO<\/jats:italic>, encoding the guanine nucleotide exchange factor, are associated with two distinct neurodevelopmental delay phenotypes: gain\u2010of\u2010function missense mutations within the spectrin repeats are causative for a severe developmental delay with macrocephaly (MIM: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/omim.org\/entry\/618825\">618825<\/jats:ext-link>), whereas loss\u2010of\u2010function missense variants in the GEF1 domain and truncating variants throughout the gene lead to a milder developmental delay and microcephaly (MIM: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/omim.org\/entry\/617061\">617061<\/jats:ext-link>). In three affected family members with mild intellectual disability\/NDD and microcephaly, we detected a novel heterozygous <jats:italic>TRIO<\/jats:italic> variant at the last coding base of exon 31 (NM_007118.4:c.4716G&gt;A). RNA analysis from patient\u2010derived lymphoblastoid cells confirmed aberrant splicing resulting in the skipping of exon 31 (r.4615_4716del), leading to an in\u2010frame deletion in the first Pleckstrin homology subdomain of the GEF1 domain: p.(Thr1539_Lys1572del). To test for a distinct gestalt, facial characteristics of the family members and 41 previously published <jats:italic>TRIO<\/jats:italic> cases were systematically evaluated via GestaltMatcher. Computational analysis of the facial gestalt suggests a distinguishable facial <jats:italic>TRIO\u2010<\/jats:italic>phenotype not outlined in the existing literature.<\/jats:p>","DOI":"10.1002\/ajmg.a.63599","type":"journal-article","created":{"date-parts":[[2024,3,22]],"date-time":"2024-03-22T12:56:21Z","timestamp":1711112181000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>RNA<\/scp> analysis and computer\u2010aided facial phenotyping help to classify a novel <i>TRIO<\/i> splice site variant"],"prefix":"10.1002","volume":"194","author":[{"given":"Sarina","family":"Schwartzmann","sequence":"first","affiliation":[{"name":"Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Freie Universit\u00e4t Berlin and Humboldt\u2010Universit\u00e4t zu Berlin, Institut f\u00fcr Medizinische Genetik und Humangenetik  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Max","family":"Zhao","sequence":"additional","affiliation":[{"name":"Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Freie Universit\u00e4t Berlin and Humboldt\u2010Universit\u00e4t zu Berlin, Institut f\u00fcr Medizinische Genetik und Humangenetik  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henrike Lisa","family":"Sczakiel","sequence":"additional","affiliation":[{"name":"Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Freie Universit\u00e4t Berlin and Humboldt\u2010Universit\u00e4t zu Berlin, Institut f\u00fcr Medizinische Genetik und Humangenetik  Berlin Germany"},{"name":"RG Development &amp; Disease Max Planck Institute for Molecular Genetics  Berlin Germany"},{"name":"Berlin Institute of Health at Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charit\u00e9 Junior Clinician Scientist Program  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriele","family":"Hildebrand","sequence":"additional","affiliation":[{"name":"Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Freie Universit\u00e4t Berlin and Humboldt\u2010Universit\u00e4t zu Berlin, Institut f\u00fcr Medizinische Genetik und Humangenetik  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1449-9909","authenticated-orcid":false,"given":"Nadja","family":"Ehmke","sequence":"additional","affiliation":[{"name":"Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Freie Universit\u00e4t Berlin and Humboldt\u2010Universit\u00e4t zu Berlin, Institut f\u00fcr Medizinische Genetik und Humangenetik  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0870-8911","authenticated-orcid":false,"given":"Denise","family":"Horn","sequence":"additional","affiliation":[{"name":"Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Freie Universit\u00e4t Berlin and Humboldt\u2010Universit\u00e4t zu Berlin, Institut f\u00fcr Medizinische Genetik und Humangenetik  Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin A.","family":"Mensah","sequence":"additional","affiliation":[{"name":"Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Freie Universit\u00e4t Berlin and Humboldt\u2010Universit\u00e4t zu Berlin, Institut f\u00fcr Medizinische Genetik und Humangenetik  Berlin Germany"},{"name":"RG Development &amp; 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