Understanding
Okur-Chung Neurodevelopmental Syndrome
Published Research
For each publication, we have the abstract provided. We provide a link to the publication and a link to our 'Research Explained'. The scientific language in published research papers can be so complex you may feel like you need a Ph.D. to understand what they are saying. To address this issue with the help of our researchers, we have a program called Research Explained. We ask researchers to explain their research in a language we can all understand.
Explore OCNDS published research below.
Clinical Phenotyping and Case Reports (24)
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Inherited loss of function variant in CSNK2A1: the oldest reported cases of Okur–Chung syndrome in a single family (2024)
Link to PublicationNo abstract available. Contact research@csnk2a1foundation.org for more information.
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Patient with a heterozygous pathogenic variant in CSNK2A1 gene: A new case to update the Okur–Chung neurodevelopmental syndrome (2024)
Link to PublicationAbstract
The autosomal dominant Okur–Chung neurodevelopmental syndrome (OCNDS: OMIM #617062) is a rare neurodevelopmental disorder first described in 2016. Features include developmental delay (DD), intellectual disability (ID), behavioral problems, hypotonia, language deficits, congenital heart abnormalities, and non-specific dysmorphic facial features. OCNDS is caused by heterozygous pathogenic variants in CSNK2A1 (OMIM *115440; NM_177559.3). To date, 160 patients have been diagnosed worldwide. The number will likely increase due to the growing use of exome sequencing (ES) and genome sequencing (GS). Here, we describe a novel OCNDS patient carrying a CSNK2A1 variant (NM_177559.3:c.140G>A; NP_808227.1:p. Arg47Gln). Phenotypically, he presented with DD, ID, generalized hypotonia, speech delay, short stature, microcephaly, and dysmorphic features such as low-set ears, hypertelorism, thin upper lip, and a round face. The patient showed several signs not yet described that may extend the phenotypic spectrum of OCNDS. These include prenatal bilateral clubfeet, exotropia, and peg lateral incisors. However, unlike the majority of descriptions, he did not present sleep disturbance, seizures or gait difficulties. A literature review shows phenotypic heterogeneity for OCNDS, whether these patients have the same variant or not. This case report is an opportunity to refine the phenotype of this syndrome and raise the question of the genotype–phenotype correlation.
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Okur-Chung neurodevelopmental syndrome: Implications for phenotype and genotype expansion
Abstract
Background
Okur-Chung neurodevelopmental syndrome (OCNDS) is a rare autosomal dominant disorder caused by pathogenic variants in CSNK2A1. It is characterized by intellectual disability, developmental delay, and multisystemic abnormalities.
Methods
We performed the whole-exome sequencing for a patient in a Chinese family. The co-segregation study using the Sanger sequencing method was performed among family members. Reverse transcription and quantitative real-time polymerase chain reaction were carried out using total RNA from blood samples of the proband and wild-type control subjects. A review of patients with OCNDS harboring CSNK2A1 pathogenic variants was conducted through a comprehensive search of the PubMed database.
Results
We identified a novel CSNK2A1 frameshift variant p.Tyr323Leufs*16 in a Chinese family. The proband, a 31-year-old female, presented with abnormal eating habits, recurrent seizures, language impairment, and intellectual disability. Her mother exhibited postnatal hernias, splenomegaly, and a predisposition to infections, but showed no significant developmental impairments or intellectual disability. Genetic studies revealed the presence of this variant in CSNK2A1 in both the proband and her mother. Transcription analysis revealed this variant may lead to nonsense-mediated mRNA decay, suggesting haploinsufficiency as a potential disease mechanism. We reviewed 47 previously reported OCNDS cases and discovered that individuals carrying CSNK2A1 null variants may exhibit a diminished frequency of symptoms linked to language deficits, dysmorphic facial features, or intellectual disability, consequently presenting an overall milder phenotype when compared to those with missense variants.
Conclusion
We report a novel frameshift variant, p.Tyr323Leufs*16, in an OCNDS family with a generally mild phenotype. This study may broaden the spectrum of clinical presentations associated with OCNDS and contribute novel insights into the genotype–phenotype correlation of this condition.
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Two novel CSNK2A1 variants associated with mild Okur-Chung neurodevelopmental syndrome phenotype (2023)
Link to PublicationAbstract
In this report, we expand the genotypic spectrum of OCNDS by reporting two novel CSNK2A1 variants, identified in two children by whole exome sequencing (WES). Both patients have African ancestors. They present with distinct, non-overlapping, subtle phenotypes, emphasizing the wide clinical variability associated with this condition. We also report a case of OCNDS caused by a de novo CSNK2A1 frameshift variant with no associated learning difficulties.
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Inherited CSNK2A1 variants in families with Okur-Chung neurodevelopmental syndrome (2023)
Link to PublicationAbstract
Okur-Chung neurodevelopmental syndrome (OCNDS) (OMIM# 617062) is an autosomal dominant disorder caused by heterozygous mutations in the CSNK2A1 gene localized on chromosome 20p13.1. The diagnosis of OCNDS is based on suggestive clinical findings and the presence of a heterozygous pathogenic variant in the CSNK2A1 gene. Developmental delays, mild-to-moderate intellectual disabilities, hypotonia, difficulty feeding, distinctive facial features, and delayed speech are the common features associated with OCNDS. Several nonspecific clinical features have also been reported in some individuals, including behavioral problems, disrupted sleep patterns, abnormal head size, seizures, and short stature. Previously reported subjects with OCNDS were diagnosed as simplex cases caused by de novo heterozygous pathogenic variants in CSNK2A1
with unaffected parents.
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Clinical Features of Okur-Chung Neurodevelopmental Syndrome: Case Report and Literature Review (2022)
Link to PublicationAbstract
Introduction: Autosomal dominant pathogenic variations in the CSNK2A1
gene cause Okur-Chung neurodevelopmental syndrome (OCNDS).
Methods: The proband and her parents were examined thoroughly and observed for any issues related to OCNDS. Furthermore, peripheral blood samples were collected from each subject for further investigations. Whole-exome sequencing identified a pathogenic variant in CSNK2A1 (NM_001895: c.62G>A, p.R21Q; rs1402734448).
Results: The proband has global developmental delay, speech disorders, epilepsy, and behavioral issues. Despite the previously reported cases, she manifested both atonic and myoclonic seizures simultaneously. Lastly, we provide a review of the reported cases with OCNDS.
Discussion: p.R21Q causes OCNDS. Further studies are highly recommended concerning this mutation to validate the results of this study and expand the knowledge regarding CSNK2A1 and the phenotypic spectrum of OCNDS.
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Identification of novel CSNK2A1 variants and the genotype-phenotype relationship in patients with Okur-Chung neurodeve
Link to PublicationAbstract
De novo germline variants of the casein kinase 2x subunit (CK2x) gene (CSNK2A1) have been reported in individuals with the congenital neuropsychiatric disorder Okur-Chung neurodevelopmental syndrome (OCNDS). Here, we report on two unrelated children with OCNDS and review the literature to explore the genotype-phenotype relationship in OCNDS.
Both children showed facial dysmorphism, growth retardation, and neuropsychiatric disorders. Using whole-exome sequencing, we identified two novel de novo CSNK2A1
variants: c.479A>G p.(HI60R) and c.238C>T p.(R80C). A search of the literature identified 12 studies that provided information on 35 CSNK2A1 variants in various protein-coding regions of CK2x. By quantitatively analyzing data related to these CSNK2A1 variants and their corresponding phenotypes, we showed for the first time that mutations in protein-coding CK2x regions appear to influence the phenotypic spectrum of OCNDS. Mutations altering the ATP/GTP-binding loop were more likely to cause the widest range of phenotypes. Therefore, any assessment of clinical spectra for this disorder should be extremely thorough. This study not only expands the mutational spectrum of OCNDS, but also provides a comprehensive overview to improve our understanding of the genotype-phenotype relationship in OCNDS.
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Report of an Asian-Indian patient with Okur-Chung Syndrome and comparison of the clinical phenotype in different ethnic groups (2021)
Link to PublicationNo abstract available. Contact research@csnk2a1foundation.org for more information.
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Identification of a novel de novo variant of CSNK2A1 gene in a boy with Okur-Chung neurodevelopmental syndrome *Article in Chinese (2020)
Link to PublicationAbstract
Objective: To analyze pathogenic variant of CSNK2A1 gene in a boy with Okur-Chung neurodevelopmental syndrome (OCNS).
Methods: The 8-year-old boy presented with growth retardation, intellectual disability and spells of breath holding. With genomic DNA extracted from peripheral blood samples of the patient and his parents, whole exome sequencing was carried out. Putative pathogenic variants were verified with Sanger sequencing. The nature and impact of detected variants were predicted through bioinformatic analysis.
Results: A novel de novo missense variant c.149A>G (p.Tyr50Cys) of the CSNK2A1 gene was identified, which was unreported previously. The variant was predicted to be pathogenic by PolyPhen-2, Mutation Taster and SIFT software. Based on a HomoloGene system, 50 loci within the CK2alpha protein are highly conserved. The change of amino acid (Cys) at position 50 has destroyed the ATP binding loop domain, causing serious damage to its function. As predicted by a Swiss PDB viewer, the variant can significantly alter the spatial structure of CK2alpha, resulting in loss of protein function.
Conclusion: The patient's condition may be attributed to the novel de novo missense variant c.149A>G (p.Tyr50Cys) of the CSNK2A1 gene.
Contact research@csnk2a1foundation.org for more information.
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Dual molecular diagnosis of tricho-rhino-phalangeal syndrome type I and Okur-Chung neurodevelopmental syndrome in one Chinese patient: a case report (2020)
Link to PublicationAbstract
Background: Okur-Chung neurodevelopmental syndrome (OCNDS) and tricho-rhino-phalangeal syndrome type I (TRPSI) are rare Mendelian diseases. OCNDS is caused by CSNK2A1 gene variants and TRPSI is caused by the TRPS1gene. However, to have two Mendelian diseases in one patient is even rarer.
Case presentation: A 6-year-10-month-old boy characterized by special facial features, short stature and mental retardation was referred to our pediatric endocrinology department. Whole-exome sequencing (WES) was done to detect the molecular basis of his disease. This patient was confirmed to carry two variants in the CSNK2A1 gene and one in the TRPS1 gene. The variant in the CSNK2A1 gene was vertically transmitted from his father, and the variant in TRPS1 gene from his mother. These two variants are classified as pathogenic and the causes of the presentation in this child. This patient’s father and mother have subsequently been diagnosed as having OCNDS and TRPSI respectively.
Conclusion: This is the first reported case of a dual molecular diagnosis of tricho-rhino-phalangeal syndrome type I and Okur-Chung neurodevelopmental syndrome in the same patient. This patient is the first published example of vertical transmission of this recurrent CSN2A1 variant from parent to child. A novel variant in the TRPS1 gene that is pathogenic was also identified. In conclusion, identification of the variants in this patient expands the phenotypes and molecular basis of dual Mendelian diseases.
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Identification of de novo CSNK2A1 and CSNK2B variants in cases of global developmental delay with seizures (2019)
Link to PublicationAbstract
Casein kinase 2 (CK2) is a serine threonine kinase ubiquitously expressed in eukaryotic cells and involved in various cellular processes. In recent studies, de novo variants in CSNK2A1 and CSNK2B, which encode the subunits of CK2, have been identified in individuals with intellectual disability syndrome. In this study, we describe four patients with neurodevelopmental disorders possessing de novo variants in CSNK2A1 or CSNK2B. Using whole-exome sequencing, we detected two de novo variants in CSNK2A1 in two unrelated Japanese patients, a novel variant c.571C>T, p.(Arg191*) and a recurrent variant c.593A>G, p.(Lys198Arg), and two novel de novo variants in CSNK2B in Japanese and Malaysian patients, c.494A>G, p.(His165Arg) and c.533_534insGT, p.(Pro179Tyrfs*49), respectively. All four patients showed mild to profound intellectual disabilities, developmental delays, and various types of seizures. This and previous studies have found a total of 20 CSNK2A1 variants in 28 individuals with syndromic intellectual disability. The hotspot variant c.593A>G, p.(Lys198Arg) was found in eight of 28 patients. Meanwhile, only five CSNK2B variants were identified in five individuals with neurodevelopmental disorders. We reviewed the previous literature to verify the phenotypic spectrum of CSNK2A1- and CSNK2B-related syndromes.
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A case of Okur-Chung syndrome caused by CSNK2A1 gene variation and review of literature *Article in Chinese (2019)
Link to PublicationAbstract
Objective: To summarize the clinical features and gene variation characteristics of a child with Okur-Chung syndrome caused by CSNK2A1 gene variation.
Methods: The medical records of one patient who was diagnosed with Okur-Chung syndrome in Department of Pediatrics, Xiangya Hospital of Central South University in July 2018 were analyzed. Using "CSNK2A1" gene as the keyword, relevant information about CSNK2A1 gene was searched at CNKI, Wangfang Data, OMIM, PubMed, ClinVar, Decipher (until August 2018). The characteristics of CSNK2A1 gene variation and the clinical phenotype of children with Okur-Chung syndrome were summarized.
Results: The boy, 1 year and 8 months old, was sent to hospital at the age of 1 year and 6 months because of delayed growth for more than 1 year. He was susceptible to cough while eating or drinking. He was also suffering from constipation and poor sleep. Physical examination showed that his body weight was 10.2 kg, microcephalus, broad nasal bridge, micrognathia and hypotonia were observed. Whole exome-sequencing test identified a de novo heterozygous variation c.524A>G (p.D175G) in CSNK2A1 gene. This was the first case report of CSNK2A1 gene variation in the mainland of China. So far, a total of 52 cases were reported worldwide (52 single nucleotide variants), including 35 cases in 7 articles, 9 cases in Decipher database and 14 cases in ClinVar database, 6 of which were also reported in PubMed. In previously reported 52 cases, there were 48 missense variants, whereas, splice and frameshift variations were found in 3 cases and 1 case, respectively. Among the variation sites, p.K198R was the most common sites (12 cases), followed by p.R47 (6 cases), p.R80H (4 cases) and p.S51 (4 cases). Among these 52 cases, only 27 cases have been elaborately described in other studies, so the clinical characteristics were summarized in 28 cases eventually (including 27 cases in the articles and this patient), 27 of whom presented severe intellectual disability or global development delay, 1 case with mild language development delay, and 19 had hypotonia; 8 had autism spectrum disorders, 5 had attention deficit hyperactivity disorder, and 9 had sleep problems. 20 had dysmorphic facial features, 10 of them had microcephalus. 16 had failure to thrive or short stature, 12 had gastrointestinal or oromotor problem, 5 had immunological problem, and 4 had skin abnormalities.
Conclusions: The main clinical feature of patients with CSNK2A1 gene variations is intellectual disability with multiple systems involved, such as microcephalus, abnormal facial shape and hypotonia. The variation of CSNK2A1 gene is the cause of Okur-Chung syndrome. Missense variation is the main cause, and P. K198R is the hotspot variation.
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Okur-Chung neurodevelopmental syndrome: Eight additional cases with implications on phenotype and genotype expansion (2018)
Link to PublicationAbstract
Okur-Chung syndrome is a neurodevelopmental condition attributed to germline CSNK2A1 pathogenic missense variants. We present 8 unreported subjects with the above syndrome, who have recognizable dysmorphism, varying degrees of developmental delay and multisystem involvement. Together with 6 previously reported cases, we present a case series of 7 female and 7 male subjects, highlighting the recognizable facial features of the syndrome (microcephaly, hypertelorism, epicanthic fold, ptosis, arched eyebrows, low set ears, ear fold abnormality, broad nasal bridge and round face) as well as frequently occurring clinical features including neurodevelopmental delay (93%), gastrointestinal (57%), musculoskeletal (57%) and immunological (43%) abnormalities. The variants reported in this study are evolutionary conserved and absent in the normal population. We observed that the CSNK2A1 gene is relatively intolerant to missense genetic changes, and most variants are within the protein kinase domain. All except 1 variant reported in this cohort are spatially located on the binding pocket of the holoenzyme. We further provide key recommendations on the management of Okur-Chung syndrome. To conclude, this is the second case series on Okur-Chung syndrome, and an in-depth review of the phenotypic features and genomic findings of the condition with suggestions on clinical management.
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Extending the phenotype associated with the CSNK2A1-related Okur-Chung syndrome-A clinical study of 11 individuals (2018)
Link to PublicationAbstract
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.
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Refining the clinical phenotype of Okur-Chung neurodevelopmental syndrome (2018)
Link to PublicationAbstract
We describe an 8-year-old Japanese boy with a de novo recurrent missense mutation in CSNK2A1, c.593A>G, that is causative of Okur–Chung neurodevelopmental syndrome. He exhibited distinctive facial features, severe growth retardation with relative macrocephaly, and friendly, hyperactive behavior. His dysmorphic features might suggest a congenital histone modification defect syndrome, such as Kleefstra, Coffin–Siris, or Rubinstein–Taybi syndromes, which are indicative of functional interactions between the casein kinase II, alpha 1 gene and histone modification factors.
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A novel de novo mutation in CSNK2A1: reinforcing the link to neurodevelopmental abnormalities and dysmorphic features (2017)
Link to PublicationNo abstract available. Contact research@csnk2a1foundation.org for more information.
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Are CSNK2A1 gene mutations associated with retinal dystrophy? Report of a patient carrier of a novel de novo splice site mutation (2017)
Link to PublicationAbstract
Neurodevelopmental disorders (NDDs) refer to a group of often severe pediatric conditions associated with impaired cognitive, sensory, and/or motor functions stemming from atypical development of the central nervous system. Although the recent development of genetic diagnostic tools, such as exome sequencing, has highlighted the prevalence of genetic anomalies in NDDs, the broad and variable and, at times, evolving clinical manifestations can render their prompt diagnosis difficult. Recently, de novo mutations in the CSNK2A1 gene, encoding for the alpha subunit of the casein kinase 2, have been found to cause a novel NDD with multisystemic involvement, termed Okur-Chung disease (MIM 617062). Clinical features include intellectual disability, microcephaly, hypotonia, and ataxia, with high inter-subject variability [1–3]. Here we report, to our knowledge for the first time, a pediatric patient carrier of a “de novo” mutation in the CSNK2A1 gene initially presenting with isolated retinal dystrophy.
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De novo mutations in CSNK2A1 are associated with neurodevelopmental abnormalities and dysmorphic features (2016)
Link to PublicationAbstract
Whole exome sequencing (WES) can be used to efficiently identify de novo genetic variants associated with genetically heterogeneous conditions including intellectual disabilities. We have performed WES for 4102 (1847 female; 2255 male) intellectual disability/developmental delay cases and we report five patients with a neurodevelopmental disorder associated with developmental delay, intellectual disability, behavioral problems, hypotonia, speech problems, microcephaly, pachygyria and dysmorphic features in whom we have identified de novo missense and canonical splice site mutations in CSNK2A1, the gene encoding CK2α, the catalytic subunit of protein kinase CK2, a ubiquitous serine/threonine kinase composed of two regulatory (β) and two catalytic (α and/or α') subunits. Somatic mutations in CSNK2A1 have been implicated in various cancers; however, this is the first study to describe a human condition associated with germline mutations in any of the CK2 subunits.
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Okur-Chung neurodevelopmental syndrome in a patient from Spain
Read Publication HereAbstract:
Okur-Chung neurodevelopmental syndrome (OCNS, MIM#617062) is a rare autosomal dominant syndrome related to CSNK2A1 mutations. It is characterized by intellectual disability, hypotonia, feeding and speech difficulties, dysmorphic features, and multisystem involvement. To date, less than 30 patients with OCNS have been described in detail in the literature, primarily in Asian populations. Here, we report a 5-year-old Spanish female with OCNS arising from a novel CSNK2A1 mutation c.149A>G, p.Tyr50Cys. Although her clinical features were compatible with OCNS syndrome, magnetic resonance imaging unexpectedly showed a duplication of the pituitary gland, a clinical finding not previously related to any known genetic condition. Other novel signs were the absence of the olfactory bulbs and multiple duplications of cervical vertebrae. We suggest that the midline abnormalities may be a significant part of this condition and lead to diagnostic suspicion. However, further descriptions are needed.
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Persistent Hyperplastic Primary Vitreous with Microphthalmia and Coloboma in a Patient with Okur-Chung Neurodevelopmental Syndrome
Read Research HereAbstract:
Okur-Chung neurodevelopmental syndrome is a rare autosomal dominant disorder caused by pathogenic variants in CSNK2A1, which encodes the alpha 1 catalytic subunit of ¬casein kinase II. This syndrome is characterized by intellectual disability, developmental delay, and multisystemic ¬abnormalities including those of the brain, extremities, and skin as well as cardiovascular, gastrointestinal, and immune systems. In this study, we describe a 5-year-old boy with a de novo novel nonsense variant in CSNK2A1, NM_001895.3:c.319C>T (p.Arg107*). He showed bilateral persistent hyperplastic primary vitreous with microphthalmia, lens dysplasia, and coloboma. Ocular manifestations are very rare in this syndrome, and this study expands the spectrum of the clinical presentations of this syndrome.
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Exome sequencing in 16 patients with pituitary stalk interruption syndrome: A monocentric study
Review Article HereAbstract:
Pituitary stalk interruption syndrome (PSIS) is a rare disorder characterized by an absent or ectopic posterior pituitary, absent or interrupted pituitary stalk and anterior pituitary hypoplasia on magnetic resonance imaging (MRI), as well in some cases a range of heterogeneous somatic anomalies. The triad can be incomplete. Here, we performed exome sequencing on 16 sporadic patients, aged 0.4 to 13.7 years diagnosed with isolated or complex PSIS. Growth hormone deficiency was isolated in 10 cases, or associated with thyrotropin deficiency in 6 others (isolated (2 cases), associated with adrenocorticotropin deficiency (1 case), gonadotropins deficiency (1 case), or multiple deficiencies (2 cases)). Additional phenotypic anomalies were present in six cases (37.5%) including four with ophthalmic disorders. In 13 patients variants were identified that may contribute to the phenotype. However, only a single individual carried a variant classified as pathogenic. This child presented with the typical clinical presentation of Okur-Chung neurodevelopmental syndrome due to a CSNK2A1 missense variant. We also identified variants in the holoprosencephaly associated genes GLI2 and PTCH1. A likely pathogenic novel splice site variant in the GLI2 gene was observed in a child with PSIS and megacisterna magna. In the remaining 11 cases 26 variants in genes associated with pituitary development or function were identified and were classified of unknown significance. Compared with syndromic forms the diagnostic yield in the isolated forms of PSIS is low. Although we identified rare or novel missense variants in several hypogonadotropic hypogonadism genes (e.g. FGF17, HS6ST1, KISS1R, CHD7, IL17RD) definitively linking them to the PSIS phenotype is premature. A major challenge remains to identify pathogenic variants in cases with isolated PSIS.
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Okur-Chung neurodevelopmental syndrome: Implications for phenotype and genotype expansion
Access Article HereAbstract:
Background: Okur-Chung neurodevelopmental syndrome (OCNDS) is a rare autosomal dominant disorder caused by pathogenic variants in CSNK2A1. It is characterized by intellectual disability, developmental delay, and multisystemic abnormalities.
Methods:
We performed the whole-exome sequencing for a patient in a Chinese family. The co-segregation study using the Sanger sequencing method was performed among family members. Reverse transcription and quantitative real-time polymerase chain reaction were carried out using total RNA from blood samples of the proband and wild-type control subjects. A review of patients with OCNDS harboring CSNK2A1 pathogenic variants was conducted through a comprehensive search of the PubMed database.
Results:
We identified a novel CSNK2A1 frameshift variant p.Tyr323Leufs*16 in a Chinese family. The proband, a 31-year-old female, presented with abnormal eating habits, recurrent seizures, language impairment, and intellectual disability. Her mother exhibited postnatal hernias, splenomegaly, and a predisposition to infections, but showed no significant developmental impairments or intellectual disability. Genetic studies revealed the presence of this variant in CSNK2A1 in both the proband and her mother. Transcription analysis revealed this variant may lead to nonsense-mediated mRNA decay, suggesting haploinsufficiency as a potential disease mechanism. We reviewed 47 previously reported OCNDS cases and discovered that individuals carrying CSNK2A1 null variants may exhibit a diminished frequency of symptoms linked to language deficits, dysmorphic facial features, or intellectual disability, consequently presenting an overall milder phenotype when compared to those with missense variants.
Conclusion:
We report a novel frameshift variant, p.Tyr323Leufs*16, in an OCNDS family with a generally mild phenotype. This study may broaden the spectrum of clinical presentations associated with OCNDS and contribute novel insights into the genotype-phenotype correlation of this condition.
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Expanding the Phenotypic Spectrum of CSNK2A1-associated Okur-Chung Neurodevelopmental Syndrome (2024 Pre-print)
Link to PublicationAuthors: Swetha Ramadesikan, Iftekhar A. Showpnil, Mohammad Marhabaie, Allison Daley, Elizabeth A. Varga, Umamaheswaran Gurusamy, Matthew T. Pastore, Emily R. Sites, Murugu Manickam, Dennis W. Bartholomew, Jesse M. Hunter, Peter White, Richard K. Wilson, Rolf W. Stottmann, Daniel C. Koboldt
ABSTRACT
De novo variants in CSNK2A1 cause autosomal dominant Okur-Chung neurodevelopmental syndrome (OCNDS). OCNDS has an evolving clinical phenotype predominantly characterized by intellectual disability, global delays, dysmorphic features, and immunological manifestations. Microcephaly, defined as a small head circumference, is not widely recognized as a classical clinical presentation. Here, we describe four individuals from three unrelated families who shared several clinical features characteristic of an underlying syndromic neurodevelopmental condition. Trio clinical exome and research genome sequencing revealed that all affected individuals had heterozygous pathogenic missense variants in CSNK2A1. Two variants (c.468T>A p.Asp156Glu and c.149A>G p.Tyr50Cys) were de novo and previously reported , but the third variant (c.137G>T p.Gly46Val) is novel, and segregated in two affected individuals in a family. This adds to growing evidence of inherited disease-causing variants in CSNK2A1, an observation reported only twice previously. A detailed phenotypic analysis of our cohort together with those individuals reported in the literature revealed that OCNDS individuals, on average, have a smaller head circumference with 1/3rd presenting with microcephaly. We also show that the incidence of microcephaly is significantly correlated with the location of the variant in the encoded protein. Our findings suggest that small head circumference is a common but under-recognized feature of OCNDS which may not be apparent at birth.
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A Case of Okur-Chung Neurodevelopmental Syndrome with a Novel, de novo Variant on the CSNK2A1 Gene in a Turkish Patient
Link to PublicationAbstract
Introduction
Okur-Chung neurodevelopmental syndrome (OCNDS; #617062) has been associated with heterozygous mutations in the CSNK2A1 gene (*115440) mapped on the chromosome’s 20p13 region.
Case Presentation
The analysis was performed on a 2-year-old patient who was admitted to our genetic diseases evaluation center by his family with a complaint of hypotonia. We detected a heterozygous NM_177559.3 (CSNK2A1):c.1139_1140dupGG (p.Met381GlyfsTer32) variant in the CSNK2A1 gene from a whole-exome sequence analysis.
Conclusion
The variant that we detected has not been reported in open-access databases to date, so it was evaluated as a novel likely pathogenic variant according to the ACMG-2015 criteria. No variant was detected upon segregation analysis of the patient’s parents; therefore, the related variant was evaluated as de novo. In this study, we offer the first report of a pathogenic frameshift variant in the CSNK2A1 gene that has a relationship with OCNDS.
Keywords: Neurodevelopmental syndrome, Hypotonia, Novel, De novo variant, Whole-exome sequencing
Variant Characterization (6)
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The Okur-Chung Neurodevelopmental Syndrome Mutation CK2K198R Leads to a Rewiring of Kinase Specificity (2022)
Link to PublicationAbstract
Okur-Chung Neurodevelopmental Syndrome (OCNDS) is caused by heterozygous mutations to the CSNK2A1
gene, which encodes the alpha subunit of casein kinase II (CK2). The most frequently occurring mutation is lysine 198 to arginine (K198R). To investigate the impact of this mutation, we first generated a high-resolution phosphorylation motif of CK2WT, including the first characterization of specificity for tyrosine phosphorylation activity. A second high resolution motif representing CK2K198R substrate specificity was also generated. Here we report for the first time the impact of the OCNDS associated CK2K198R mutation. Contrary to prior speculation, the mutation does not result in a loss of function, but rather shifts the substrate specificity of the kinase. Broadly speaking the mutation leads to 1) a decreased preference for acidic residues in the +1 position, 2) a decreased preference for threonine phosphorylation, 3) an increased preference for tyrosine phosphorylation, and 4) an alteration of the tyrosine phosphorylation specificity motif. To further investigate the result of this mutation we have developed a probability-based scoring method, allowing us to predict shifts in phosphorylation in the K198R mutant relative to the wild type kinase. As an initial step we have applied the methodology to the set of axonally localized ion channels in an effort to uncover potential alterations of the phosphoproteome associated with the OCNDS disease condition.
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Predictive functional, statistical and structural analysis of CSNK2A1 and CSNK2B variants linked to neurodevelopmental diseases (2022)
Link to PublicationAbstract
Okur-Chung Neurodevelopmental Syndrome (OCNDS) and Poirier-Bienvenu Neurodevelopmental Syndrome (POBINDS) were recently identified as rare neurodevelopmental disorders. OCNDS and POBINDS are associated with heterozygous mutations in the CSNK2A1
and CSNK2B genes which encode CK2α, a serine/threonine protein kinase, and CK2β, a regulatory protein, respectively, which together can form a tetrameric enzyme called protein kinase CK2. A challenge in OCNDS and POBINDS is to understand the genetic basis of these diseases and the effect of the various CK2⍺ and CK2β mutations. In this study we have collected all variants available to date in CSNK2A1
and CSNK2B, and identified hotspots. We have investigated CK2⍺ and CK2β missense mutations through prediction programs which consider the evolutionary conservation, functionality and structure or these two proteins, compared these results with published experimental data on CK2α and CK2β mutants, and suggested prediction programs that could help predict changes in functionality of CK2α mutants. We also investigated the potential effect of CK2α and CK2β mutations on the 3D structure of the proteins and in their binding to each other. These results indicate that there are functional and structural consequences of mutation of CK2α and CK2β, and provide a rationale for further study of OCNDS and POBINDS-associated mutations. These data contribute to understanding the genetic and functional basis of these diseases, which is needed to identify their underlying mechanisms.
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Structural and Enzymological Evidence for an Altered Substrate Specificity in Okur-Chung Neurodevelopmental Syndrome Mutant CK2αLys198Arg (2022)
Abstract
Specific de novo mutations in the CSNK2A1 gene, which encodes CK2α, the catalytic subunit of protein kinase CK2, are considered as causative for the Okur-Chung neurodevelopmental syndrome (OCNDS). OCNDS is a rare congenital disease with a high phenotypic diversity ranging from neurodevelopmental disabilities to multi-systemic problems and characteristic facial features. A frequent OCNDS mutation is the exchange of Lys198 to Arg at the center of CK2α's P+1 loop, a key element of substrate recognition. According to preliminary data recently made available, this mutation causes a significant shift of the substrate specificity of the enzyme. We expressed the CK2αLys198Arg recombinantly and characterized it biophysically and structurally. Using isothermal titration calorimetry (ITC), fluorescence quenching and differential scanning fluorimetry (Thermofluor), we found that the mutation does not affect the interaction with CK2β, the non-catalytic CK2 subunit, and that the thermal stability of the protein is even slightly increased. However, a CK2αLys198Arg crystal structure and its comparison with wild-type structures revealed a significant shift of the anion binding site harboured by the P+1 loop. This observation supports the notion that the Lys198Arg mutation causes an alteration of substrate specificity which we underpinned here with enzymological data.
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Okur-Chung neurodevelopmental syndrome-linked CK2α variants have reduced kinase activity (2021)
Link to PublicationAbstract
The Okur-Chung neurodevelopmental syndrome, or OCNDS, is a newly discovered rare neurodevelopmental disorder. It is characterized by developmental delay, intellectual disability, behavioral problems (hyperactivity, repetitive movements and social interaction deficits), hypotonia, epilepsy and language/verbalization deficits. OCNDS is linked to de novo mutations in CSNK2A1, that lead to missense or deletion/truncating variants in the encoded protein, the protein kinase CK2α. Eighteen different missense CK2α mutations have been identified to date; however, no biochemical or cell biological studies have yet been performed to clarify the functional impact of such mutations. Here, we show that 15 different missense CK2α mutations lead to varying degrees of loss of kinase activity as recombinant purified proteins and when mutants are ectopically expressed in mammalian cells. We further detect changes in the phosphoproteome of three patient-derived fibroblast lines and show that the subcellular localization of CK2α is altered for some of the OCNDS-linked variants and in patient-derived fibroblasts. Our data argue that reduced kinase activity and abnormal localization of CK2α may underlie the OCNDS phenotype.
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Prevalence and architecture of de novo mutations in developmental disorders (2017)
Link to PublicationAbstract
The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year.
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Improvement of variant reclassification in genetic neurodevelopmental conditions
Read Article HereAbstract: Purpose
Limited knowledge about disease mechanisms, few published cases, and the lack of functional assessment of variants for neurodevelopmental genetic disorders challenge diagnostic classification for variants and increase the frequency of variants of uncertain significance (VUS). Because inheritance patterns aid in variant interpretation for neurodevelopmental conditions, genetic testing including only the proband leads to larger numbers of VUS than testing strategies that include the parents.
Methods
We reinterpreted genetic variants submitted to the Simons Searchlight research registry using American College of Medical Genetics and Genomics variant interpretation guidelines, familial cascade testing, and literature curation with annual VUS reevaluation.
Results
Simons Searchlight has independently evaluated 2834 genetic laboratory reports; 20.4% of variants (1.7% copy-number variants and 18.7% monogenic variants) were reclassified with 230 upgrades and 173 downgrades in pathogenicity. Of 351 monogenic VUS on the original clinical test report, 25.4% were reclassified as likely pathogenic or pathogenic. VUS in SCN2A, SLC6A1, or STXBP1 were more likely to have VUS reclassified compared with variants in other genes.
Conclusion
Regular reevaluation of neurodevelopmental genetic variants can be helpful because relevant variant reclassifications occur frequently and may affect clinical care. Simons Searchlight contributes to the international neurodevelopmental community by systematically reviewing uncertain variants annually and providing reclassified variants to participants, researchers, and ClinVar.
Relevant Literature Reviews (3)
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Okur-Chung Neurodevelopmental Syndrome GeneReview (2022)
Link to PublicationDr. Okur wrote a chapter in GeneReviews about OCNDS.
GeneReviews is regarded as a reference resource among geneticists in terms of learning about the scope of a given condition, molecular genetic causes, and surveillance and management guidelines. Dr. Okur encourages you to share this chapter with your clinicians for follow-up directions. He said, "It may not reflect every problem that families encounter, partly because the chapter is limited to published data, but regular updates will be done every 2-3 years and should there be a significant discovery. We are so grateful to every family in the Okur-Chung Neurodevelopmental Syndrome community for teaching us daily about this syndrome, which enabled us to share this knowledge with the broader community.”
Abstract
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.
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Comparing Two Neurodevelopmental Disorders Linked to CK2: Okur-Chung Neurodevelopmental Syndrome and Poirier-Bienvenu Neurodevelopmental Syndrome-Two Sides of the Same Coin? (2022)
Link to PublicationAbstract
In recent years, variants in the catalytic and regulatory subunits of the kinase CK2 have been found to underlie two different, yet symptomatically overlapping neurodevelopmental disorders, termed Okur-Chung neurodevelopmental syndrome (OCNDS) and Poirier-Bienvenu neurodevelopmental syndrome (POBINDS). Both conditions are predominantly caused by de novo missense or nonsense mono-allelic variants. They are characterized by a generalized developmental delay, intellectual disability, behavioral problems (hyperactivity, repetitive movements and social interaction deficits), hypotonia, motricity and verbalization deficits. One of the main features of POBINDS is epilepsies, which are present with much lower prevalence in patients with OCNDS. While a role for CK2 in brain functioning and development is well acknowledged, these findings for the first time clearly link CK2 to defined brain disorders. Our review will bring together patient data for both syndromes, aiming to link symptoms with genotypes, and to rationalize the symptoms through known cellular functions of CK2 that have been identified in preclinical and biochemical contexts. We will also compare the symptomatology and elaborate the specificities that distinguish the two syndromes.
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Protein kinase CK2: a potential therapeutic target for diverse human diseases (2021)
Abstract
CK2 is a constitutively active Ser/Thr protein kinase, which phosphorylates hundreds of substrates, controls several signaling pathways, and is implicated in a plethora of human diseases. Its best documented role is in cancer, where it regulates practically all malignant hallmarks. Other well-known functions of CK2 are in human infections; in particular, several viruses exploit host cell CK2 for their life cycle. Very recently, also SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has been found to enhance CK2 activity and to induce the phosphorylation of several CK2 substrates (either viral and host proteins). CK2 is also considered an emerging target for neurological diseases, inflammation and autoimmune disorders, diverse ophthalmic pathologies, diabetes, and obesity. In addition, CK2 activity has been associated with cardiovascular diseases, as cardiac ischemia–reperfusion injury, atherosclerosis, and cardiac hypertrophy. The hypothesis of considering CK2 inhibition for cystic fibrosis therapies has been also entertained for many years. Moreover, psychiatric disorders and syndromes due to CK2 mutations have been recently identified. On these bases, CK2 is emerging as an increasingly attractive target in various fields of human medicine, with the advantage that several very specific and effective inhibitors are already available. Here, we review the literature on CK2 implication in different human pathologies and evaluate its potential as a pharmacological target in the light of the most recent findings.
Studies Analyzing Neurodevelopmental Syndromes, Including OCNDS (2)
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Quantifying neurobehavioral profiles across neurodevelopmental genetic syndromes and idiopathic neurodevelopmental disorders
Link to PublicationAbstract
Aim: To examine neurobehavioral findings in three genetic syndromes (PTEN hamartoma tumor syndrome, Malan syndrome [mutations in the NFIX gene], and SYNGAP1-related disorder), a mixed group of other neurodevelopmental genetic syndromes (NDGS), idiopathic neurodevelopmental disorder, and neurotypical control participants.
Method: Using a longitudinal case-control design, caregivers reported neurobehavioral information for 498 participants (PTEN hamartoma tumor syndrome n = 112, Malan syndrome n = 24, SYNGAP1-related disorder n = 47, other NDGS n = 72, idiopathic neurodevelopmental disorder n = 54, neurotypical siblings n = 74, and unrelated neurotypical control participants n = 115) at three timepoints (baseline, and 1-month and 4-month follow-ups) using the online-administered Neurobehavioral Evaluation Tool (NET).
Results: NET scales had good scale and test-retest reliability. Unique patterns of neurobehavioral findings emerged, with SYNGAP1-related disorder and Malan syndrome showing generally more severe symptom and skill patterns than for other groups of patients. Patterns could be partly accounted for by estimated cognitive level, speech level, and the presence of autism spectrum disorder. However, even when accounting for these factors, group differences remained. Reliable change indices are reported.
Interpretation: Genetic syndromes associated with neurodevelopmental disorders present with unique neurobehavioral profiles that can inform selection of outcome measures in future clinical trials. The NET may be a useful screening and monitoring instrument in clinical practice, where frequent in-person clinic attendance is difficult for many patients.
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Motor phenotypes associated with genetic neurodevelopmental disorders
Link to PublicationAbstract
Objective: There is a growing number of monogenic disorders implicated in neurodevelopmental disorders (NDDs), including autism spectrum disorder and intellectual disability. Motor impairment is frequently seen in these disorders, although not clearly defined. We aimed to characterize the motor phenotype of genetic NDDs.
Methods: We analyzed data from Simons Searchlight, collecting information on patients with genetic NDDs. Data analyzed included Vineland Adaptive Behavior Scales Second Edition (Vineland-II) motor standard scores, motor milestones and tone abnormalities.
Results: In total, 959 patients with 57 genetic disorders were included. Disorders associated with Vineland-II motor standard score <56 included GRIN2B-related disorder (mean standard score = 53.5), HNRNPH2-related disorder (mean standard score = 55.8) and SCN2A-related disorder (mean standard score = 49.9). The only genetic condition with a mean age of sitting unsupported ≥18 months was GRIN1-related disorder (mean age = 26.3 months). Genetic conditions with a mean age of walking independently ≥36 months included CTNNB1-related disorder (mean age = 37.4 months) and HNRNPH2-related disorder (mean age = 41.9 months). Tone abnormalities included hypotonia in 83% (577/696), hypertonia in 16% (112/696), a diagnosis of cerebral palsy (CP) in 10% (73/696) and a diagnosis specifically of spastic CP in 3% (23/696).
Interpretation: Patients with genetic NDDs have a spectrum of motor impairment, which warrant further characterization.
OCNDS Models (1)
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Missense mutation in the activation segment of the kinase CK2 models Okur-Chung neurodevelopmental disorder and alters the hippocampal glutamatergic synapse
Link to PublicationAuthors: Jose M. Cruz-Gamero, Demetra Ballardin, Barbara Lecis, Chun-Lei Zhang, Laetitia Cobret, Alexander Gast, Severine Morisset-Lopez, Rebecca Piskorowski, Dominique Langui, Joachim Jose, Guillaume Chevreux and Heike Rebholz
Publication Date: October 4, 2024
Research Explained By: Gabrielle Rushing, PhD, Chief Scientific Officer, CSNK2A1 Foundation
Link to article: https://www.nature.com/articles/s41380-024-02762-8.epdf?sharing_token=IGKbBMfTRJwkHXNrz6XVANRgN0jAjWel9jnR3ZoTv0O3AuiV8n52MaL6bjUSUDN7ruiSJpT93z8ee3VuyYInUYUm86BA8EdIB-Ef2t_eWEoYHRbmLiTam70gMN-AyH-s78k8iyJ8A839355QQmEqe0GjU2HT7dsU7SlKo1kw7AA%3D
Abstract: Exome sequencing has enabled the identification of causative genes of monogenic forms of autism, amongst them, in 2016, CSNK2A1, the gene encoding the catalytic subunit of the kinase CK2, linking this kinase to Okur-Chung Neurodevelopmental Syndrome (OCNDS), a newly described neurodevelopmental condition with many symptoms resembling those of autism spectrum disorder. Thus far, no preclinical model of this condition exists. Here we describe a knock-in mouse model that harbors the K198R mutation in the activation segment of the α subunit of CK2. This region is a mutational hotspot, representing one-third of patients.
These mice exhibit behavioral phenotypes that mirror patient symptoms. Homozygous knock-in mice die mid-gestation while heterozygous knock-in mice are born at half of the expected mendelian ratio and are smaller in weight and size than wildtype littermates. Heterozygous knock-in mice showed alterations in cognition and memory-assessing paradigms, enhanced stereotypies, altered circadian activity patterns, and nesting behavior. Phosphoproteome analysis from brain tissue revealed alterations in the phosphorylation status of major pre- and postsynaptic proteins of heterozygous knock-in mice. In congruence, we detect reduced synaptic maturation in hippocampal neurons and attenuated long-term potentiation in the hippocampus of knock-in mice. Taken together, heterozygous knock-in mice (CK2αK198R/+) exhibit significant face validity, presenting ASD-relevant phenotypes, synaptic deficits, and alterations in synaptic plasticity, all of which strongly validate this line as a mouse model of OCNDS.
Other (2)
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A complex of distal appendage-associated kinases linked to human disease regulates ciliary trafficking and stability (2021)
Link to PublicationAbstract
Cilia biogenesis is a complex, multistep process involving the coordination of multiple cellular trafficking pathways. Despite the importance of ciliogenesis in mediating the cellular response to cues from the microenvironment, we have only a limited understanding of the regulation of cilium assembly. We previously identified Tau tubulin kinase 2 (TTBK2) as a key regulator of ciliogenesis. Here, using CRISPR kinome and biotin identification screening, we identify the CK2 catalytic subunit CSNK2A1 as an important modulator of TTBK2 function in cilia trafficking. Superresolution microscopy reveals that CSNK2A1 is a centrosomal protein concentrated at the mother centriole and associated with the distal appendages. CSNK2A1 mutant cilia are longer than those of control cells, showing instability at the tip associated with ciliary actin cytoskeleton changes. These cilia also abnormally accumulate key cilia assembly and SHH-related proteins. De novo mutations of CSNK2A1 were recently linked to the human genetic disorder Okur-Chung neurodevelopmental syndrome (OCNDS). Consistent with the role of CSNK2A1 in cilium stability, we find that expression of OCNDS-associated Csnk2a1 variants in wild-type cells causes ciliary structural defects. Our findings provide insights into mechanisms involved in ciliary length regulation, trafficking, and stability that in turn shed light on the significance of cilia instability in human disease.
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Patient organization perspective: a research roadmap for Okur-Chung Neurodevelopmental Syndrome
ButtonAbstract: Okur-Chung neurodevelopmental syndrome (OCNDS) is an ultra-rare disorder caused by variants in the CSNK2A1 gene. CSNK2A1 encodes for the alpha subunit of casein kinase 2 (CK2), a serine/threonine kinase critical in neural development. CK2 is implicated in many human pathologies, including viral infections, cancer, inflammation, cardiovascular, neurodegenerative, and psychiatric diseases. However, the mechanism of action for the CSNK2A1 variants observed in OCNDS is not fully understood, although studies suggest a loss of function or altered substrate specificity. There are no approved treatments for OCNDS, and current treatments focus on symptom management. The CSNK2A1 Foundation was established in 2018 and aims to find a cure for OCNDS and provide support to affected individuals. OCNDS presents with symptoms at varying severity, including developmental delay/intellectual disabilities, autism, disrupted sleep, speech delays/inability to speak, short stature, and, in ~25% of cases, epilepsy. The foundation has developed a research toolbox that is readily available to researchers worldwide and has awarded ~$1 million in grant funding. These efforts have provided valuable insights into CK2 biology and the natural history of OCNDS. However, additional efforts are needed to fully characterize the disease mechanism and investigate potential treatment interventions. Continued investigation into CK2 and its role in neural development holds promise for a better understanding of OCNDS and related disorders in the future. To accelerate research, we have developed a research roadmap highlighting key focus areas of landscape analysis/toolbox expansion, biomarker development, and therapeutic testing through a series of steps that are nonlinear; we expect these efforts to guide decision-making for therapeutic exploration whether that be drug repurposing, gene therapy, novel drug discovery, or a combination. In this perspective article, we describe OCNDS and the CSNK2A1 gene, highlight gaps in OCNDS research, discuss the research roadmap, and offer the founder's perspective on our growth and future opportunities.