CSNK2A1 – Okur-Chung Neurodevelopmental Syndrome

Okur-Chung neurodevelopmental syndrome (OCNDS) is an autosomal dominant disorder caused by heterozygous pathogenic variants in CSNK2A1 ([HGNC:2457]) and characterized by intellectual disability, global developmental delay, hypotonia, behavioral abnormalities, and dysmorphic features. Over 160 patients have been diagnosed worldwide, with both de novo and inherited variants demonstrating consistent segregation in multiple families ([PMID:38711237], [PMID:29383814]).

Genetic studies have identified a spectrum of CSNK2A1 variants including missense, nonsense, frameshift, and splice-site changes. Recurrent missense substitutions such as c.593A>G (p.Lys198Arg) and novel frameshift variants like c.967dup (p.Tyr323LeufsTer16) have been reported in unrelated probands ([PMID:29619237], [PMID:38444259]). Familial transmission of c.593A>G (p.Lys198Arg) confirms autosomal dominant inheritance with vertical transmission observed in both father–child and mother–child pairs ([PMID:32746809], [PMID:39497417]).

In-depth phenotypic analyses across multiple cohorts (n=11 in the Deciphering Developmental Disorders Study) revealed core features such as intellectual disability, hypotonia, feeding and speech difficulties, seizures, and midline abnormalities including pituitary duplication and coloboma, expanding the clinical spectrum of OCNDS ([PMID:31729156], [PMID:35221879]).

Functional assays demonstrate that CSNK2A1 missense mutations impair the catalytic activity and alter substrate specificity of CK2α. Fifteen patient-derived variants show reduced kinase activity and abnormal subcellular localization ([PMID:33944995]). Structural studies of the Lys198Arg mutant reveal a shifted P+1 loop and altered anion-binding site, supporting a mechanism of disrupted substrate recognition rather than complete loss of function ([PMID:35445078], [PMID:35517865]).

No conflicting evidence has been reported; all functional and clinical data converge on haploinsufficiency and dominant-negative effects as disease mechanisms. Further studies are needed to elucidate modifier genes and long-term outcomes.

Key Take-home: CSNK2A1 pathogenic variants cause a well-defined autosomal dominant neurodevelopmental syndrome with recognizable clinical features and robust functional evidence supporting diagnostic and therapeutic exploration.

References

• Human genome variation • 2018 • Refining the clinical phenotype of Okur-Chung neurodevelopmental syndrome. [PMID:29619237]
• BMC medical genetics • 2020 • Dual molecular diagnosis of tricho-rhino-phalangeal syndrome type I and Okur-Chung neurodevelopmental syndrome in one Chinese patient: a case report. [PMID:32746809]
• American journal of medical genetics. Part A • 2020 • Okur-Chung neurodevelopmental syndrome in a patient from Spain. [PMID:31729156]
• Molecular syndromology • 2022 • Persistent Hyperplastic Primary Vitreous with Microphthalmia and Coloboma in a Patient with Okur-Chung Neurodevelopmental Syndrome. [PMID:35221879]
• Molecular syndromology • 2022 • Clinical Features of Okur-Chung Neurodevelopmental Syndrome: Case Report and Literature Review. [PMID:36588763]
• Molecular syndromology • 2024 • A Case of Okur-Chung Neurodevelopmental Syndrome with a Novel, de novo Variant on the CSNK2A1 Gene in a Turkish Patient. [PMID:38357263]
• Molecular genetics & genomic medicine • 2024 • Okur-Chung neurodevelopmental syndrome: Implications for phenotype and genotype expansion. [PMID:38444259]
• American journal of medical genetics. Part A • 2024 • Patient with a heterozygous pathogenic variant in CSNK2A1 gene: A new case to update the Okur-Chung neurodevelopmental syndrome. [PMID:38711237]
• HGG advances • 2024 • Expanding the phenotypic spectrum of CSNK2A1-associated Okur-Chung neurodevelopmental syndrome. [PMID:39497417]
• Human genetics • 2021 • Okur-Chung neurodevelopmental syndrome-linked CK2α variants have reduced kinase activity. [PMID:33944995]
• Frontiers in molecular biosciences • 2022 • Structural and Enzymological Evidence for an Altered Substrate Specificity in Okur-Chung Neurodevelopmental Syndrome Mutant CK2 Lys198Arg. [PMID:35445078]
• Frontiers in molecular biosciences • 2022 • The Okur-Chung Neurodevelopmental Syndrome Mutation CK2K198R Leads to a Rewiring of Kinase Specificity. [PMID:35517865]

Evidence Based Scoring (AI generated)