Chung W, Okur V. Okur-Chung Neurodevelopmental Syndrome. 2022 Jun 9. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. PMID: 35679446.
Excerpt
Clinical characteristics: Individuals with Okur-Chung neurodevelopmental syndrome (OCNDS) frequently have nonspecific clinical features, delayed language development, motor delay, intellectual disability (typically in the mild-to-moderate range), generalized hypotonia starting in infancy, difficulty feeding, and nonspecific dysmorphic facial features. Developmental delay affects all areas of development, but language is more impaired than gross motor skills in most individuals. Intellectual disability has been reported in about three quarters of individuals. Less common findings may include kyphoscoliosis, postnatal short stature, disrupted circadian rhythm leading to sleep disturbance, seizures, and poor coordination.
Diagnosis/testing: The diagnosis of OCNDS is established in a proband with suggestive findings and a heterozygous pathogenic variant in CSNK2A1 identified by molecular genetic testing.
Management: Treatment of manifestations: Feeding therapy and consideration of gastrostomy tube placement in those with persistent feeding issues; consideration of growth hormone therapy (as directed by an endocrinologist) in those with short stature and evidence of partial growth hormone deficiency; standard treatment of epilepsy (as directed by a neurologist) with anti-seizure medication; consideration of intravenous immune globulin treatment (as directed by an immunologist) for demonstrated hypogammaglobulinemia; physical therapy / occupational therapy / rehabilitation medicine for those with hypotonia and/or motor coordination issues; standard supportive developmental therapies; standard treatment of scoliosis, constipation, congenital heart defects, renal anomalies / pelviectasis, and sleep disorders.
Surveillance: At each visit: measure growth parameters, growth velocity, and nutritional status; monitor for signs of ongoing feeding issues / safety of oral intake and constipation; assess new neurologic manifestations (seizures, changes in tone, movement disorders, poor coordination); monitor developmental progress, behavior, and educational needs; monitor for evidence of frequent or unusual infections and for signs and symptoms of sleep disturbance. Every one to three years: ophthalmology evaluation.
Genetic counseling: OCNDS disorder is expressed in an autosomal dominant manner and typically caused by a de novo CSNK2A1 pathogenic variant. Therefore, the risk to other family members is presumed to be low. Rarely, individuals diagnosed with OCNDS have the disorder as the result of a CSNK2A1 pathogenic variant inherited from an affected parent or an unaffected parent with low-level mosaicism in the blood. Once a CSNK2A1 pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible.
Owen CI, Bowden R, Parker MJ, Patterson J, Patterson J, Price S, Sarkar A, Castle B, Deshpande C, Splitt M, Ghali N, Dean J, Green AJ, Crosby C; Deciphering Developmental Disorders Study; Tatton-Brown K. Extending the phenotype associated with the CSNK2A1-related Okur-Chung syndrome-A clinical study of 11 individuals. Am J Med Genet A. 2018 May;176(5):1108-1114. doi: 10.1002/ajmg.a.38610. Epub 2018 Jan 31. PMID: 29383814.
Abstract
Variants in the Protein Kinase CK2 alpha subunit, encoding the CSNK2A1 gene, have previously been reported in children with an intellectual disability and dysmorphic facial features syndrome: now termed the Okur-Chung neurodevelopmental syndrome. More recently, through trio-based exome sequencing undertaken by the Deciphering Developmental Disorders Study (DDD study), a further 11 children with de novo CSNK2A1 variants have been identified. We have undertaken detailed phenotyping of these patients. Consistent with previously reported patients, patients in this series had apparent intellectual disability, swallowing difficulties, and hypotonia. While there are some shared facial characteristics, the gestalt is neither consistent nor readily recognized. Congenital heart abnormalities were identified in nearly 30% of the patients, representing a newly recognized CSNK2A1 clinical association. Based upon the clinical findings from this study and the previously reported patients, we suggest an initial approach to the management of patients with this recently described intellectual disability syndrome.
Zhang N, Han M, Zhao T, Tang X, Wang Z, Du Y, Wang L. Identification and functional analysis of a novel CSNK2A1 frameshift variant in stillbirth. Front Genet. 2025 Oct 27;16:1692704. doi: 10.3389/fgene.2025.1692704. PMID: 41216289; PMCID: PMC12597092.
Abstract
Background: Casein Kinase II Subunit Alpha (CK2α), the catalytic subunit of protein kinase CK2, is encoded by CSNK2A1. This kinase catalyzes substrate phosphorylation and regulates diverse cellular processes including cell cycle progression, apoptosis, and transcription. CSNK2A1 is associated with Okur-Chung Neurodevelopmental Syndrome (OCNS, OMIM: 617062). Although CSNK2A1 functional deficiency is implicated in impaired embryonic development, prenatal case reports remain scarce.
Methods: Clinical data and fetal umbilical cord blood samples were collected. Whole-genome sequence (WGS) was used for potential pathogenic variants identification, followed by Sanger sequencing to validate the variant. Bioinformatic tools were employed to predict the 3D structure of the variant. Wild-type and mutant CSNK2A1 overexpression plasmids were constructed to investigate the functional consequences of the variant.
Result: A 33-year-old pregnant woman without adverse obstetric history. At 34+4 weeks, ultrasound showed an intracranial abnormal echoes, multiple cardiovascular anomalies, and stillbirth had occurred at 35 weeks. WGS identified a novel frameshift mutation c.1020_1021delAG (p.Gly342Glnfs*57) in the CSNK2A1 gene. Bioinformatics analysis indicated structural modification in mutant proteins. In vitro kinase assays showed that the variant did not impair kinase activity. Quantitative analysis demonstrated significantly elevated mutant mRNA levels but reduced protein expression compared to wild-type. Elevated ubiquitination in mutants potentially explains diminished CSNK2A1 protein abundance.
Conclusion: We report a novel CSNK2A1 frameshift mutation that significantly reduces protein expression and impairs gene function. These findings expand our understanding of CSNK2A1's genetic diversity and underscore the importance of comprehensive functional analyses to achieve accurate diagnosis. This study facilitates prenatal diagnosis of CSNK2A1-related disorders and informs clinical decision-making for carriers.
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