Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders.

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• RHOBTB2 gene variants are associated with neurodevelopmental disorders.
• Missense variants in the BTB domain of RHOBTB2 cause severe developmental and epileptic encephalopathy.

Purpose of the Study:

• To investigate the clinical and molecular spectrum of RHOBTB2-related neurodevelopmental disorders.
• To identify genotype-phenotype correlations for RHOBTB2 variants.
• To explore the functional consequences of RHOBTB2 missense variants.

Main Methods:

• International collaboration to assemble individuals with pathogenic RHOBTB2 variants.
• Western blotting to assess the in vitro consequences of missense variants.
• Analysis of de novo heterozygous and biallelic variants.

Main Results:

• De novo heterozygous missense variants in the BTB domain cause severe developmental and epileptic encephalopathy.
• De novo missense variants in the GTPase domain result in variable neurodevelopmental phenotypes.
• GTPase domain variants do not impair RHOBTB2 proteasomal degradation in vitro.
• Biallelic splice-site and truncating variants lead to variable neurodevelopmental phenotypes, indicating loss-of-function pathogenicity.

Conclusions:

• RHOBTB2 variants contribute to a spectrum of neurodevelopmental disorders.
• Genotype-phenotype correlations are identified based on variant location and functional consequences.
• Both autosomal dominant and recessive inheritance patterns are implicated in RHOBTB2-related phenotypes.