A Novel Homozygous TBC1D2B Variant Disrupts Functional Domains and Suggests Impaired Rab-GTPase Regulation in Neurodevelopmental Disorder
Küçük Resim Yok
Tarih
2025
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Wiley
Erişim Hakkı
info:eu-repo/semantics/closedAccess
Özet
Recent 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.
Açıklama
Anahtar Kelimeler
Genetic Variation, Gingival Overgrowth, Neurodevelopmental Disorder, Seizure, Whole-Exome Sequencing
Kaynak
Developmental Neurobiology
WoS Q Değeri
Q2
Scopus Q Değeri
Q1
Cilt
85
Sayı
4
