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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\n                    <jats:italic>TBC1D2B<\/jats:italic>\n                    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\n                    <jats:italic>TBC1D2B<\/jats:italic>\n                    variants c.2584C&gt;T;\u00a0p.(Arg862Cys) and c.2758C&gt;T;\u00a0p.(Arg920*). In subject-derived fibroblasts,\n                    <jats:italic>TBC1D2B<\/jats:italic>\n                    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&gt;T splice site variant,\n                    <jats:italic>TBC1D2B<\/jats:italic>\n                    transcript analysis revealed aberrantly spliced mRNAs and a drastically reduced\n                    <jats:italic>TBC1D2B<\/jats:italic>\n                    mRNA level in leukocytes. The molecular spectrum included 12 different\n                    <jats:italic>TBC1D2B<\/jats:italic>\n                    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\n                    <jats:italic>TBC1D2B<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1038\/s41431-024-01563-5","type":"journal-article","created":{"date-parts":[[2024,2,19]],"date-time":"2024-02-19T03:02:05Z","timestamp":1708311725000},"page":"558-566","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Loss of TBC1D2B causes a progressive neurological disorder with gingival overgrowth"],"prefix":"10.1038","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2610-0600","authenticated-orcid":false,"given":"Frederike L.","family":"Harms","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica Erin","family":"Rexach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4900-9877","authenticated-orcid":false,"given":"Stephanie","family":"Efthymiou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Busra","family":"Aynekin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00fcseyin","family":"Per","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4968-9326","authenticated-orcid":false,"given":"Ayten","family":"G\u00fcle\u00e7","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9575-0722","authenticated-orcid":false,"given":"Sheela","family":"Nampoothiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo","family":"Sampaio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rani","family":"Sachdev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6383-8201","authenticated-orcid":false,"given":"Radka","family":"Stoeva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kasiani","family":"Myers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loren D. 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Written informed consent for the publication of photographs was obtained for five subjects.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}