OCNDS core features are conserved across variants, with loop-region mutations driving greater symptom burden.

Introduction: Okur-Chung Neurodevelopmental Syndrome (OCNDS) is an ultra-rare genetic disorder caused by Methods: We analyzed natural history data from 48 individuals with pathogenic or likely pathogenic Results: All individuals reported speech/language delay, with additional common features including global developmental delay, neurological symptoms, and gastrointestinal issues. Variants in loop regions were associated with significantly younger age at diagnosis and a higher frequency of hypotonia. Mutations in the glycine-rich loop-known to bind both ATP and the regulatory CK2β subunit-were linked to significantly higher symptom burden and more non-seizure neurological symptoms. No significant differences were observed between variant locations for core features such as sleep issues, intellectual disability, or speech delay.. Discussion: Our findings suggest a core OCNDS symptom profile that is conserved across genotypes, with loop-region variants contributing to increased symptom burden. These results reinforce the relevance of conserved functional domains in driving phenotype severity and support the use of mutation location as a potential biomarker to stratify patients for therapeutic prioritization. Further studies incorporating functional assays and larger cohorts are needed to elucidate mechanisms of variant-specific pathogenesis and guide personalized intervention strategies.