RHOBTB2

Inheritance Pattern: AD

Disease ID:MONDO:0033373

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0033373

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0033373

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: ClinGen

*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).

Inheritance Pattern: AD

Disease ID:MONDO:0033373

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*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).

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: LiferaOmics

ClinGen RHOBTB2–related complex neurodevelopmental disorder (AR) – Definitive – Approval: 2024 ClinGen Evidence Breakdown Genetic Evidence = 12.0 points (max reached) Based on: • PMID: 33456446 • PMID: 37165955 Experimental Evidence = 0 points (no experimental evidence used in the ClinGen AR curation) ClinGen Total = 12.0 Genetic Evidence – Our Case Family 1 – one proband. Case-level (biallelic predicted null in AR model; homozygous frameshift; no consanguinity → no −0.5 applied) = 1.5; Segregation = 0; Case-control = 0 Family 1 total = 1.5 Our Case Total = 1.5 / 12 Updated Total Genetic Evidence (ClinGen + Our Case) ClinGen genetic evidence: 12.0 (cap reached) Our additional case: +1.5 Updated genetic total = 12.0 (cap maintained) Experimental Evidence (unchanged from ClinGen) ClinGen experimental evidence = 0 Updated Overall Score Genetic evidence = 12.0 Experimental evidence = 0 Updated total = 12.0 Brief curation summary (AR scope) ClinGen classifies RHOBTB2 as Definitive for autosomal recessive complex neurodevelopmental disorder, supported by multiple independent probands with biallelic loss-of-function variants (nonsense/frameshift/splice), reported across PMIDs 33456446 and 37165955, with replication over time and no contradictory evidence noted.