Epilepsja związana z mutacjami genu ANKRD11 - analiza 163 pacjentów

OBJECTIVE: Ankyrin repeat domain 11 gene (ANKRD11) is the key disease gene for autosomal dominant KBG syndrome, and a subset of affected individuals develop epilepsy. However, comprehensive characterization of epilepsy-related phenotypes and genotype-phenotype correlations in ANKRD11 variant carriers remains limited. We aimed to integrate a single-center cohort with previously reported cases to delineate the epilepsy phenotype spectrum, evaluate genotype-phenotype associations, and provide clinical information for ANKRD11-related epilepsy. METHODS: Whole exome sequencing was performed in nine unrelated individuals identified at our center. In addition, a systematic search of PubMed (keywords: "ANKRD11" AND "epilepsy") was performed up to October 2025, and eligible cases were aggregated for pooled analyses of clinical features. RESULTS: We identified nine individuals with heterozygous ANKRD11 variants at our center; four had epilepsy, and three variants were novel. In silico analyses suggested stronger predicted deleterious effects for missense variants within repression domain (RD; including RD1 and RD2)-related regions, and localization to RD2 may be associated with potential genotype-phenotype correlations. In a pooled cohort of 163 individuals with ANKRD11 variants and epilepsy, seizure onset occurred at a median age of 4.0 years (interquartile range = 1.5-8.0). Focal and generalized epilepsies were similarly represented, and absence seizures were reported in 22.8%. Brain magnetic resonance imaging (MRI) abnormalities were observed in 45.9% of individuals with available data; 63.2% of patients in the overall cohort achieved seizure freedom, with 36.8% exhibiting drug-resistant epilepsy. Frameshift variants predominated (60.1%), and variants showed domain-specific enrichment, with missense variants clustering in RD2 and truncating variants enriched outside RD2. Individuals with missense variants tended to have later onset, normal MRI, and higher seizure control rates. SIGNIFICANCE: This integrated analysis expands the mutational spectrum of ANKRD11 and provides a consolidated genotype-phenotype landscape of ANKRD11-related epilepsy. Variant class and domain-specific clustering patterns, together with differences in clinical profiles and outcomes, support domain-informed variant interpretation and may improve clinical counseling and management for patients.