Natural History Study

Abstract

Introduction: Okur-Chung Neurodevelopmental Syndrome (OCNDS) is an ultra-rare genetic disorder caused by de novo mutations in the CSNK2A1 gene, which encodes the catalytic subunit of protein kinase CK2α. OCNDS is characterized by global developmental delay, intellectual disability, speech and language deficits, and other multi-system symptoms. Although prior reports have described considerable phenotypic variability, the relationship between specific CK2α variant locations and symptom presentation remains poorly defined.

Methods: We analyzed natural history data from 48 individuals with pathogenic or likely pathogenic CSNK2A1 missense variants enrolled in Simons Searchlight. Variants were categorized by their location in conserved CK2α protein domains, specifically distinguishing between loop (e.g., glycine-rich loop, p+1 loop) and non-loop regions. We evaluated symptom burden across organ systems, age at diagnosis, and adaptive functioning using caregiver-reported surveys.

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.

Research Explained

Authors: Neil R. Ming, Deanna Noble, Steven Chussid, Alban Ziegler, Wendy K. Chung

Abstract

Background: Children with neurodevelopmental disorders (NDDs) often have poor oral health and dental abnormalities. An increasing number of genes have been associated with neurodevelopmental conditions affecting the oral cavity, but the specific dental features associated with many genes remain unknown.

Aim: To report the types and frequencies of dental manifestations in children with neurodevelopmental conditions of known genetic cause. Design: A 30- question survey assesing ectodermal and dental features was administered through Simons Searchlight, with which formed a recontactable cohort of individuals with genetic NDDs often associated with autism spectrum disorder (ASD).

Results: Data were collected from a largely paediatric population with 620 affected individuals across 39 genetic conditions and 145 unaffected siblings without NDDs for comparison. Drooling, difficulty accessing dental care, late primary teeth eruption, abnormal primary and permanent teeth formation, misshapen nails, and hair loss were more frequent in individuals with NDDs. Additionally, we evidenced an association between three new pathogenic gene variant/oral manifestation pairs: CSNK2A1/unusual primary teeth, DYRK1A/late primary teeth eruption, and PPP2R5D/sialorrhea.

Conclusion: Our results demonstrate that genetic NDDs caused by mutations in CSNK2A1, DYRK1A, and PP2R5D are associated with unique dental manifestations, and knowledge of these features can be helpful to personalize dental care.

KEYWORDS: brain function, dental health survey(s), genetics, personalized medicine, tooth development

Research Explained