RHOBTB2 was first reported in relation to autosomal recessive complex neurodevelopmental disorder in 2020 (Maddirevula et al., PMID: 33456446). Phenotypic features in individuals with biallelic RHOBTB2 variants include intellectual disability, hypotonia and/or hypertonia, microcephaly, seizures, and movement disorders. Reported seizure types include absence, febrile, and generalized tonic clonic seizures with onset typically in neonatal period and infancy (PMID: 37165955). Of note, there have also been many reported cases of individuals with de novo heterozygous missense 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 AD RHOBTB2 variants have been curated separately by the Epilepsy GCEP.
Eight homozygous variants reported in eight probands from 2 publications are included in this curation (PMIDs: 33456446, 37165955). Additionally, one individual with compound heterozygous nonsense and canonical splice site variants has also been reported (PMID: 37165955). The mechanism of pathogenicity appears to be loss of function, as reported variants are nonsense, frameshift and splice site in probands with biallelic variants (PMID: 37165955). There was no experimental evidence utilized for this curation.
In summary, there is definitive evidence supporting the relationship between RHOBTB2 and AR 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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