RHOBTB2 – Developmental and Epileptic Encephalopathy Type 64

Developmental and epileptic encephalopathy type 64 (DEE64; MONDO:0033373) is an autosomal dominant neurodevelopmental disorder characterized by early-onset refractory seizures, global developmental delay, severe intellectual disability, postnatal microcephaly, and movement abnormalities. RHOBTB2 (HGNC:18756) encodes an atypical Rho GTPase that acts as a substrate adaptor for the CUL3 ubiquitin ligase complex, regulating proteasomal degradation of signaling proteins.

To date, 60 unrelated probands with de novo RHOBTB2 missense variants have been reported, with approximately 50% clustering at Arg483 and Arg511 in the BTB domain (60 cases) (PMID:39831600). Hotspot variants p.Arg483His, p.Arg511Gln, and p.Arg511Trp each account for >10% of cases.

A representative variant is c.1532G>A (p.Arg511Gln), identified de novo by WES and confirmed by Sanger sequencing in an infant presenting with DEE64 (PMID:39831600).

All reported pathogenic variants are de novo, with no evidence of transmission in affected families, underscoring full penetrance and strong genotype-phenotype correlation.

Functional studies demonstrate that BTB-domain mutants (e.g., p.Arg485Cys, p.Arg489Gln, p.Arg461His) resist CUL3-mediated degradation and accumulate in Neuro-2a cells (PMID:29768694). In Drosophila, overexpression of RhoBTB recapitulates seizure susceptibility and locomotor defects, while fly transcriptomics and human iPSC-derived neuron patch-clamp assays reveal deregulated ion channels (including the SCN1A orthologue) and increased excitability in BTB-domain variants (PMID:29276004; PMID:39849855).

These data establish a Strong gene-disease association based on 60 de novo probands, consistent hotspot clustering, and concordant functional evidence. RHOBTB2 testing is recommended for patients with early-onset epileptic encephalopathy to enable precise diagnosis and inform prognosis.

Key take-home: De novo BTB-domain RHOBTB2 variants impair ubiquitin-mediated turnover, drive neuronal hyperexcitability, and underlie DEE64 clinical features.

References

• Molecular genetics & genomic medicine • 2025 • RHOBTB2 Variant p.Arg511Gln Causes Developmental and Epileptic Encephalopathy Type 64 in an Infant: A Case Report and Hotspot Variant Analysis. PMID:39831600
• Human mutation • 2018 • De novo variants in RHOBTB2, an atypical Rho GTPase gene, cause epileptic encephalopathy. PMID:29768694
• American journal of human genetics • 2018 • Missense Variants in RHOBTB2 Cause a Developmental and Epileptic Encephalopathy in Humans, and Altered Levels Cause Neurological Defects in Drosophila. PMID:29276004
• Human molecular genetics • 2025 • Deregulated ion channels contribute to RHOBTB2-associated developmental and epileptic encephalopathy. PMID:39849855

Evidence Based Scoring (AI generated)