To date, there have been 13 papers published on Okur-Chung Neurodevelopmental Syndrome. Below are links to the papers.


Okur-Chung Neurodevelopmental Syndrome-linked CK2a variants have reduced kinase activity

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.

A complex of distal appendage-associated kinases linked to human disease regulates ciliary trafficking and stability

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.

Identification of de novo CSNK2A1 and CSNK2B variants in cases of global developmental delay with seizures

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.

Are CSNK2A1 gene mutations associated with retinal dystrophy

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.

Refining the Clinical Phenotype of Okur-Chung Neurodevelopmental Syndrome

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.

De novo Mutations in CSNK2A1 are Associated with Neurodevelopmental Abnormalities and Dysmorphic Features

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.

Okur-Chung Neurodevelopmental Syndrome Eight Additional Cases with Implications on Phenotype and Genotype Expansion

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.

Extending the Phenotype Associated with the CSNK2A1-Related Okur-Chung Syndrome-A Clinical Study of 11 Individuals

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.

Dual molecular diagnosis of tricho-rhino-phalangeal syndrome type I and Okur-Chung neurodevelopmental syndrome in one Chinese patient: a case report

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.

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.

Okur-Chung neurodevelopmental syndrome in a patient from Spain

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 an 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.

A case of Okur-Chung syndrome caused by CSNK2A1 gene variation and review of literature

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.

A novel de novo mutation in CSNK2A1: reinforcing the link to neurodevelopmental abnormalities and dysmorphic features

Prevalence and architecture of de novo mutations in developmental disorders

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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