RHOBTB2 was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2016 (Lopes et al., PMID 26740508). Phenotypic features in individuals with de novo missense RHOBTB2 variants include intellectual disability, microcephaly, seizures, paroxysmal movement disorders, dystonia, chorea, dyskinesia, dysmorphic features and abnormal brain MRI findings. Reported seizure types include febrile, generalized tonic clonic, myoclonic, and focal seizures, with onset in neonatal period and infancy (Langhammer et al, PMID: 37165955). Of note, there have also been reported cases of individuals with biallelic loss of function variants in RHOBTB2 and complex neurodevelopmental disorder. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and molecular mechanism, with the autosomal recessive (AR) presentation being primarily loss of function variants and the autosomal dominant (AD) presentation being primarily missense variants. Therefore, the curations for AD and AR complex neurodevelopmental disorder have been split, and cases with AR RHOBTB2 variants have been curated separately by the Epilepsy GCEP.
Fourteen missense variants reported in 24 individuals from five publications are included in this curation (PMIDs: 26740508, 29276004, 29768694, 33504645, 37165955). Of note, many of these variants are reported to be de novo. Genotype-phenotype correlation has been demonstrated; individuals with pathogenic variants in the two BTB domains generally have more severe to profound intellectual disability with epilepsy and movement disorder, while de novo pathogenic missense variants in the GTPase domain are associated with more variable neurodevelopmental presentations with or without epilepsy (PMID: 37165955). The mechanism of pathogenicity of the missense variants in RHOBTB2 is not well understood, and there was no experimental evidence utilized for this curation.
In summary, there is definitive evidence supporting the relationship between RHOBTB2 and AD complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Epilepsy GCEP on the meeting date January 16, 2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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