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Early onset or syndromic epilepsy v4.191 TBC1D2B Sarah Leigh edited their review of gene: TBC1D2B: Added comment: TBC1D2B variants have been associated with Neurodevelopmental disorder with seizures and gingival overgrowth (OMIM:619323) and as definitive Gen2Phen gene for TBC1D2B-related neurodevelopmental disorder. So far, 11 TBC1D2B variants have been reported in 8 unrelated families. Global developmental delay (HP:0001263) was reported in 5/8 families, mental deterioration (HP:0001268) was seen in 5/8 families and seizures (HP:0001250) were reported in 8/8 families (four of these were controlled with medication)(PMID: 38374468).; Changed rating: GREEN
Early onset or syndromic epilepsy v4.191 TBC1D2B Sarah Leigh Publications for gene: TBC1D2B were set to 32623794
Early onset or syndromic epilepsy v4.190 TBC1D2B Sarah Leigh Phenotypes for gene: TBC1D2B were changed from Global developmental delay; Intellectual disability; Seizures; Gingival overgrowth; Behavioral abnormality; Abnormality of the mandible; Abnormality of brain morphology; Abnormality of the eye; Hearing abnormality to Neurodevelopmental disorder with seizures and gingival overgrowth, OMIM:619323; neurodevelopmental disorder with seizures and gingival overgrowth, MONDO:0859148
Early onset or syndromic epilepsy v2.519 TBC1D2B Eleanor Williams Tag gene-checked tag was added to gene: TBC1D2B.
Early onset or syndromic epilepsy v2.491 TBC1D2B Sarah Leigh Tag for-review was removed from gene: TBC1D2B.
Early onset or syndromic epilepsy v2.491 TBC1D2B Sarah Leigh commented on gene: TBC1D2B
Early onset or syndromic epilepsy v2.490 TBC1D2B Sarah Leigh Source Expert Review Green was added to TBC1D2B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Early onset or syndromic epilepsy v2.214 TBC1D2B Arina Puzriakova Tag for-review tag was added to gene: TBC1D2B.
Early onset or syndromic epilepsy v2.214 TBC1D2B Arina Puzriakova Classified gene: TBC1D2B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.214 TBC1D2B Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Updating rating from Grey to Amber based on one publication (PMID:32623794).

There are sufficient cases to rate this gene Green at the next GMS panel update (added 'for-review' tag) - all 4 individuals (3 families) present seizures, although the age of onset is variable (19-years, 18-months, 3-months).
Early onset or syndromic epilepsy v2.214 TBC1D2B Arina Puzriakova Gene: tbc1d2b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.122 TBC1D2B Konstantinos Varvagiannis gene: TBC1D2B was added
gene: TBC1D2B was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TBC1D2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBC1D2B were set to 32623794
Phenotypes for gene: TBC1D2B were set to Global developmental delay; Intellectual disability; Seizures; Gingival overgrowth; Behavioral abnormality; Abnormality of the mandible; Abnormality of brain morphology; Abnormality of the eye; Hearing abnormality
Penetrance for gene: TBC1D2B were set to Complete
Review for gene: TBC1D2B was set to GREEN
Added comment: Harms et al (2020 - PMID: 32623794) report on 3 unrelated individuals with biallelic pLoF TBC1D2B variants.

Features included cognitive impairment (mild ID in one case, regression at the age of 12y in another, hypotonia and delayed milestones in a third aged 8m), seizures (3/3 - variable age of onset) and/or gingival overgrowth (2/3 - prior to initiation of AEDs). Other findings included behavioral abnormalities, mandibular anomalies, abnormal brain imaging and ophthalmologic or (rarely) audiometric evaluations.

All were born to non-consanguineous couples and additional investigations were performed in some.

Variants were identified by WES or trio WGS, with Sanger confirmation/compatible segregation analyses.

In line with the pLoF variants, mRNA studies in fibroblasts from 2 unrelated affected individuals demonstrated significantly reduced (~80-90%) TBC1C2D mRNA levels compared to controls, restored following cycloheximide treatment. Protein was absent in patient fibroblasts.

TBC-domain containing GTPase activating proteins are known as key regulators of RAB GTPase activity. TBC1D2B was shown to colocalize with RAB5-positive endocytic vesicles. CRISPR/Cas9-mediated ko of TBC1D2B in HeLa cells suggested a role in EGF receptor endocytosis and decreased cell viability of TBC1D2B-deficient HeLa cells upon serum deprivation.

Genes encoding other TBC domain-containg GTPase-activating proteins, e.g. TBC1D7 and TBC1D20, TBC1D24 are associated with recessive neurodevelopmental disorders (with ID and/or seizures) and the pathophysiological defect in TBC1D2B-related disorder (deficit in vesicle trafficking and/or cell survival) is proposed to be similar to that of TBC1D24.

Overall this gene can be considered for inclusion with amber/green rating in the ID panel and green in epilepsy panel.
Sources: Literature