Clinical and genetic spectrum of RHOBTB2-related disorders: A study integrating Chinese and international cohorts for genotype-phenotype correlations and clinical subtyping.

Objective

This study was undertaken to characterize the clinical and genetic spectrum of RHOBTB2-related disorders (RHOBTB2-RDs) in a Chinese population, explore genotype-phenotype correlations, and develop a refined clinical framework to improve diagnosis and management.

Methods

We conducted a comprehensive analysis by integrating data from 12 Chinese patients (five retrospective, seven from literature) with 79 international cases from published studies. Genetic analysis focused on variant classification and hotspot identification. Standardized phenotypic data extraction was performed, followed by systematic classification and correlation analyses.

Results

In the Chinese cohort, all variants were de novo missense mutations, with 75% in the Broad-complex, Tramtrack, and Bric-à-brac (BTB) domain and conserved hotspots (e.g., p.Arg483His). Across the combined cohort (N = 91), RHOBTB2-RDs presented a broad phenotypic spectrum. As an exploratory proposal, we introduce paroxysmal encephalopathy with weakness (PEW) as a potential novel clinical phenotypic cluster, strongly associated with BTB domain variants. A practical subtyping framework was proposed: the BTB subtype (severe developmental and epileptic encephalopathy [DEE] with prominent paroxysmal features, often necessitating aggressive seizure management), the truncating/splicing subtype (primarily intellectual disability/developmental delay and movement disorders with epilepsy, requiring focused neurodevelopmental support), the guanosine triphosphatase subtype (a mixed phenotype with a generally more favorable neurodevelopmental course), and the interdomain subtype (frequently associated with PEW alongside DEE or paroxysmal movement disorders).

Significance

This study systematically characterizes RHOBTB2-RDs in Chinese patients, confirming conserved pathogenic hotspots across ethnicities and identifying population-specific features. The proposed clinical subtyping framework and PEW diagnostic criteria provide valuable tools for improving diagnostic accuracy and guiding personalized management of RHOBTB2-RDs.