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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
Early onset or syndromic epilepsy v1.191 TBC1D20 Rebecca Foulger Source Wessex and West Midlands GLH was added to TBC1D20.
Early onset or syndromic epilepsy v1.190 TBC1D20 Rebecca Foulger Source NHS GMS was added to TBC1D20.
Early onset or syndromic epilepsy v1.189 TBC1D20 Rebecca Foulger edited their review of gene: TBC1D20: Added comment: Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: Alison Callaway and John Taylor. Suggested gene rating: Amber. ; Changed rating: AMBER
Early onset or syndromic epilepsy v1.188 TBC1D20 Tracy Lester reviewed gene: TBC1D20: Rating: AMBER; Mode of pathogenicity: ; Publications: 25476608; Phenotypes: Warburg micro syndrome 4, 615663; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.726 TBC1D20 Rebecca Foulger Marked gene: TBC1D20 as ready
Early onset or syndromic epilepsy v0.726 TBC1D20 Rebecca Foulger Gene: tbc1d20 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.726 TBC1D20 Rebecca Foulger Tag watchlist tag was added to gene: TBC1D20.
Early onset or syndromic epilepsy v0.726 TBC1D20 Rebecca Foulger Classified gene: TBC1D20 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.726 TBC1D20 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber: Variants in TBC1D20 are currently probable in DD-G2P for causing Warburg micro syndrome 4. Warburg micro syndrome 4 can present with seizures, but currently only 2 unrelated families reported in PMID:24239381 (including febrile seizures in 1 patient). Therefore require further epileptic cases before rating as diagnostic.
Early onset or syndromic epilepsy v0.726 TBC1D20 Rebecca Foulger Gene: tbc1d20 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.725 TBC1D20 Rebecca Foulger Phenotypes for gene: TBC1D20 were changed from Warburg micro syndrome 4, MIM#615663; seizures to Warburg micro syndrome 4, 615663; seizures
Early onset or syndromic epilepsy v0.724 TBC1D20 Rebecca Foulger Phenotypes for gene: TBC1D20 were changed from to Warburg micro syndrome 4, MIM#615663; seizures
Early onset or syndromic epilepsy v0.723 TBC1D20 Rebecca Foulger commented on gene: TBC1D20
Early onset or syndromic epilepsy v0.723 TBC1D20 Rebecca Foulger Publications for gene: TBC1D20 were set to
Early onset or syndromic epilepsy v0.718 TBC1D20 Rebecca Foulger Mode of inheritance for gene: TBC1D20 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy TBC1D20 Zornitza Stark reviewed gene: TBC1D20
Early onset or syndromic epilepsy TBC1D20 Sarah Leigh Added gene to panel