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| Early onset or syndromic epilepsy v1.191 | RHOBTB2 | Rebecca Foulger Source Wessex and West Midlands GLH was added to RHOBTB2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.190 | RHOBTB2 | Rebecca Foulger Source NHS GMS was added to RHOBTB2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.189 | RHOBTB2 | Rebecca Foulger reviewed gene: RHOBTB2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.188 | RHOBTB2 | Tracy Lester reviewed gene: RHOBTB2: Rating: GREEN; Mode of pathogenicity: ; Publications: 29276004; Phenotypes: Epileptic encephalopathy early infantile, 618004; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.920 | RHOBTB2 | Sarah Leigh Marked gene: RHOBTB2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.920 | RHOBTB2 | Sarah Leigh Added comment: Comment when marking as ready: Associated with phenotype in OMIM and not in Gen2Phen. At least 6 variants identified in 8 unrelated cases. In vitro functional studies suggest that pathogenicity results from increased expression or reduced degradation of the variant peptides in affected individuals (PMID 29276004). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.920 | RHOBTB2 | Sarah Leigh Gene: rhobtb2 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.920 | RHOBTB2 | Sarah Leigh Classified gene: RHOBTB2 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.920 | RHOBTB2 | Sarah Leigh Gene: rhobtb2 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.919 | RHOBTB2 | Sarah Leigh Phenotypes for gene: RHOBTB2 were changed from Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly to Epileptic encephalopathy, early infantile, 64 618004 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v0.676 | RHOBTB2 |
Konstantinos Varvagiannis gene: RHOBTB2 was added gene: RHOBTB2 was added to Genetic Epilepsy Syndromes. Sources: Expert Review,Literature Mode of inheritance for gene: RHOBTB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: RHOBTB2 were set to 29276004; 29768694; 26740508 Phenotypes for gene: RHOBTB2 were set to Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly Penetrance for gene: RHOBTB2 were set to unknown Mode of pathogenicity for gene: RHOBTB2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: RHOBTB2 was set to GREEN Added comment: PMID: 29276004 reports on 10 unrelated patients with de novo pathogenic missense variants in RHOBTB2. The phenotype in all individuals was compatible with a developmental and epileptic encephalopathy including early-onset seizures, severe intellectual disability, postnatal onset microcephaly (6/10) and movement disorders (8/10). The variants occured as de novo events and clustered within the BTB-domain encoding region (within and between the 2 BTB domains). Three missense variants were recurrent and/or concerned the same residue (p.Arg483His in 4 individuals, Arg511Gln was reported in 2, and Arg511Trp was was found in another 2 individuals). Functional studies in HEK293 cells suggested increased abundance of the mutant protein secondary to decreased proteasome degradation. Using Drosophila as a model organism, altered expression of RhoBTB (the single ortholog of the 3 vertebrate paralogs, closest to RHOBTB2) was shown to result in neurological phenotypes. RhoBTB overexpression in particular was associated with increased bang sensitivity (which was not the case or milder in the case if knockdown of this gene) and impaired performance upon the negative geotaxis assay, similar to the human neurological phenotypes. Altered RhoBTB dosage was shown to be associated with impaired dendrite development. As commented by the authors, these results as well as the clustering of missense variants and the pLI score of 0.51 reported for RHOBTB2 are consistent with altered protein function (due to the missense variants) rather than haploinsufficiency or loss-of-function. PMID: 29768694 describes 3 additional individuals, all found to harbor de novo missense variants again within the BTB-domain encoding region. Two of the variants had been reported in the previous study (Arg511Gln and Arg483His) while the third was a private one (Arg507Cys). The phenotype was similar to the previous descriptions. Functional studies were suggestive of impaired degradation of the mutant protein by the CUL3 complex although this was not secondary to decreased binding with CUL3. PMID: 26740508 (cited by the two aforementioned publications) reports briefly on an individual with de novo missense variant in the same region of RHOBTB2 (Asn510Asp) and Rett-like phenotype. RHOBTB2 is included in gene panels for intellectual disability offered by different diagnostic laboratories. As a result the gene can be considered for inclusion in the intellectual disability and epilepsy panels as green. Sources: Expert Review, Literature |
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