Loss of TBC1D2B causes a progressive neurological disorder with gingival overgrowth

Biallelic loss-of-function variants in TBC1D2B have been reported in five subjects with cognitive impairment and seizures with or without gingival overgrowth. TBC1D2B belongs to the family of Tre2-Bub2-Cdc16 (TBC)-domain containing RAB-specific GTPase activating proteins (TBC/RABGAPs). Here, we repo...

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Published in:	European journal of human genetics : EJHG Vol. 32; no. 5; pp. 558 - 566
Main Authors:	Harms, Frederike L, Rexach, Jessica Erin, Efthymiou, Stephanie, Aynekin, Busra, Per, Hüseyin, Güleç, Ayten, Nampoothiri, Sheela, Sampaio, Hugo, Sachdev, Rani, Stoeva, Radka, Myers, Kasiani, Pena, Loren D M, Kalfa, Theodosia A, Chard, Marisa, Klassen, Megan, Pries, Megan, Kutsche, Kerstin
Format:	Journal Article
Language:	English
Published:	England Nature Publishing Group 01-05-2024 Springer International Publishing
Subjects:	Adolescent Adult Atrophy Autophagy Cerebellum Child Child, Preschool Cognitive ability Female Fibrous dysplasia Gingiva Gingival Overgrowth - genetics Gingival Overgrowth - pathology GTPase-Activating Proteins - genetics Humans Leukocytes Loss of Function Mutation Male Mandible Neurodegenerative diseases Neuroimaging Neurological diseases Pedigree Seizures Seizures - genetics Seizures - pathology Siblings Ventricle Ventricles (cerebral)
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Summary:	Biallelic loss-of-function variants in TBC1D2B have been reported in five subjects with cognitive impairment and seizures with or without gingival overgrowth. TBC1D2B belongs to the family of Tre2-Bub2-Cdc16 (TBC)-domain containing RAB-specific GTPase activating proteins (TBC/RABGAPs). Here, we report five new subjects with biallelic TBC1D2B variants, including two siblings, and delineate the molecular and clinical features in the ten subjects known to date. One of the newly reported subjects was compound heterozygous for the TBC1D2B variants c.2584C>T; p.(Arg862Cys) and c.2758C>T; p.(Arg920*). In subject-derived fibroblasts, TBC1D2B mRNA level was similar to control cells, while the TBC1D2B protein amount was reduced by about half. In one of two siblings with a novel c.360+1G>T splice site variant, TBC1D2B transcript analysis revealed aberrantly spliced mRNAs and a drastically reduced TBC1D2B mRNA level in leukocytes. The molecular spectrum included 12 different TBC1D2B variants: seven nonsense, three frameshifts, one splice site, and one missense variant. Out of ten subjects, three had fibrous dysplasia of the mandible, two of which were diagnosed as cherubism. Most subjects developed gingival overgrowth. Half of the subjects had developmental delay. Seizures occurred in 80% of the subjects. Six subjects showed a progressive disease with mental deterioration. Brain imaging revealed cerebral and/or cerebellar atrophy with or without lateral ventricle dilatation. The TBC1D2B disorder is a progressive neurological disease with gingival overgrowth and abnormal mandible morphology. As TBC1D2B has been shown to positively regulate autophagy, defects in autophagy and the endolysosomal system could be associated with neuronal dysfunction and the neurodegenerative disease in the affected individuals.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Report-3 ObjectType-Case Study-4
ISSN:	1018-4813 1476-5438 1476-5438
DOI:	10.1038/s41431-024-01563-5