A Novel Homozygous TBC1D2B Variant Disrupts Functional Domains and Suggests Impaired Rab-GTPase Regulation in Neurodevelopmental Disorder

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dc.contributor.authorOzturk, Murat
dc.contributor.authorArslan, Cahide Bulut
dc.contributor.authorAkbulut, Ekrem
dc.contributor.authorHabiloglu, Esra
dc.contributor.authorYayli, Esra
dc.contributor.authorUyguner, Zehra Oya
dc.date.accessioned2026-06-19T06:41:18Z
dc.date.available2026-06-19T06:41:18Z
dc.date.issued2025
dc.departmentMalatya Turgut Özal Üniversitesi
dc.description.abstractRecent reports have linked biallelic loss-of-function variants in the TBC1D2B gene to neurodevelopmental disorder with seizures and gingival overgrowth (NEDSGO) (OMIM 619323), a rare condition characterized by seizures and gingival hyperplasia. However, due to the limited number of reported cases, the phenotypic diversity of this syndrome remains poorly characterized. This study reports four affected children from a consanguineous family in T & uuml;rkiye, in whom a novel variant in this gene was identified. All individuals underwent clinical examination, electroencephalography (EEG), brain magnetic resonance imaging (MRI), histopathological evaluation, and genetic analyses. A novel homozygous truncating variant in the TBC1D2B gene was identified. In silico protein structure modeling was performed to investigate the potential impact of the variant. The identified c.323_324delinsAA; p.(Phe108Ter) variant causes premature protein truncation, resulting in the loss of key functional domains, such as Rab-GAP-TBC, coiled-coil, and PH (pleckstrin homology). All patients exhibited developmental delay (DD), epileptic seizures, gingival fibromatosis, and craniofacial anomalies. The growth delay seen in both of our patients, also described in an earlier case with the same gene variant, suggests that this may be a clinical feature of the syndrome. Binding pocket analysis revealed marked reductions in putative protein interaction regions, suggesting a loss-of-function effect due to the mutation. These findings reveal previously unrecognized aspects of both the genetic and clinical spectrum of NEDSGO syndrome caused by variants in the TBC1D2B gene. The resulting data underscore that disruption of structural protein regions directly contributes to the phenotype of this rare disorder.
dc.identifier.doi10.1002/dneu.22998
dc.identifier.issn1932-8451
dc.identifier.issn1932-846X
dc.identifier.issue4
dc.identifier.orcid0000-0002-7526-9835
dc.identifier.pmid40898781
dc.identifier.scopus2-s2.0-105015055770
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://doi.org/10.1002/dneu.22998
dc.identifier.urihttps://hdl.handle.net/20.500.12899/6184
dc.identifier.volume85
dc.identifier.wosWOS:001585548200011
dc.identifier.wosqualityQ2
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherWiley
dc.relation.ispartofDevelopmental Neurobiology
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.snmzKA_WOS_20260612
dc.subjectGenetic Variation
dc.subjectGingival Overgrowth
dc.subjectNeurodevelopmental Disorder
dc.subjectSeizure
dc.subjectWhole-Exome Sequencing
dc.titleA Novel Homozygous TBC1D2B Variant Disrupts Functional Domains and Suggests Impaired Rab-GTPase Regulation in Neurodevelopmental Disorder
dc.typeArticle

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