OCNDS Core Features Are Conserved Across Variants, with Loop-Region Mutations Driving Greater Symptom Burden

Elena D Bagatelas¹Maahin Manzoor Khan²Gabrielle V Rushing^2*

• ¹Vanderbilt Brain Institute, School of Medicine, Vanderbilt University, Nashville, Tennessee, United States
• ²CSNK2A1 Foundation, San Francisco, United States

Okur-Chung neurodevelopmental syndrome (OCNDS) is an ultra-rare genetic disorder caused by heterozygous mutations in the CSNK2A1 gene encoding the casein kinase 2 alpha subunit (CK2α), a protein critical for many cellular processes. OCNDS is characterized by a spectrum of clinical features, including global developmental delay, intellectual disabilities, speech delay, sleep issues, hypotonia, and behavioral challenges. This study leverages Simons Searchlight natural history data to assess genotype-phenotype correlations in OCNDS. While previous studies highlight wide phenotypic variability across OCNDS patients, our analysis suggests a core set of symptoms that are universal across OCNDS patients that can guide therapeutic prioritization including speech/language delay, cognitive symptoms, sleep issues, and gastrointestinal symptoms. Prior work has noted clustering of OCNDS-associated missense mutations in conserved functional domains of the CK2α protein however, this study is the first to show that individuals with mutations within conserved loop regions of CK2α are associated with a higher frequency of hypotonia symptoms and earlier age of OCNDS diagnosis. Additionally, mutations affecting the CK2α region involved in binding both the CK2 beta subunit (CK2β) and ATP, the Glycine-rich loop), were associated with a significantly higher overall symptom burden and a greater number of neurological (non-seizure) symptoms compared to other missense variants. This analysis aims to enhance the understanding of the natural history of OCNDS, inform future research directions, and guide therapeutic development. Together, our data expand on previous OCNDS genotype-phenotype correlations and highlight the need for additional studies to ascertain functional changes that particular mutations exert on the CK2α protein.