Variants in the CSNK2B gene are known to cause Poirier-Bienvenu neurodevelopmental syndrome (POBINDS). Since its first report in 2017, nearly 100 cases have been documented. Epileptic seizures and intellectual disabilities are core symptoms of POBINDS. While the CSNK2B genotype and phenotype exhibit increasing diversity, the genotype-phenotype correlation remains unclear. In this study, we identified a novel CSNK2B heterozygous mutation NM_001320.7:c.268A > C (p.Thr90Pro) in a child with Jeavons syndrome, classified as a likely pathogenic under ACMG guidelines. Computational analyses predicted that the change of c.268A > C (p. Thr90Pro) might have an impact on the stability of the protein. This pathogenic mutation enriches the spectrum of CSNK2B gene mutations and suggests that CSNK2B may be a causative gene for Jeavons syndrome.

Poirier-Bienvenu neurodevelopmental syndrome is a neurodevelopmental disorder associated with de novo variants of the CSNK2B gene, characterized by intellectual disability, developmental delay, frequent seizures and more. While the majority of variants are nonsense variants leading to abortion of protein translation and no or truncated CK2β, many pathogenic missense variants also exist. We investigated the effect of four variants on CK2 holoenzyme formation and activity. We show that variants in the Zinc-finger region leads to reduced protein stability and altered subcellular localization. The instability is partly mediated by proteasomal and lysosomal degradation. We further show that homodimerization of these CK2β variants (p.Arg111Pro, p.Cys137Phe), localized within the Zinc-finger domain, is significantly reduced, while CK2α binding appears not affected. Other variants, p.Asp32Asn and p.Arg86Cys, did not affect stability or CK2β/α binding. For these mutants, the key to understanding the pathological mechanism may depend on external factors, such as altered protein-protein interaction. We conclude that Zinc-finger domain variants appear to destabilize the protein and affect holoenzyme formation, effectively reducing the pool of competent holoCK2. In the context of POBINDS, our findings suggest that Zinc-finger domain variants are likely to affect cells similarly to truncating and splicing variants with reduced translation of full-length CK2β.

CSNK2B deficiency underlies the pathogenesis of Poirier-Bienvenu neurodevelopmental syndrome (POBINDS). In this study, we present four cases of pediatric seizures caused by de novo variants in CSNK2B, with the aim to reinforce the clinical and variant data pertaining to early genetic factors associated with epilepsy. Trio whole exome sequencing were used to detect variants in the proband and her family members, and bioinformatics annotation was performed for the variant. Sanger sequencing and CSNK2B cDNA sequencing were employed to ascertain the carrier status of additional family members and evaluate the potential impact of variants on splicing. All four cases presented with epilepsy as the initial manifestation, accompanied by global developmental delay, particularly in language and motor developmental delay. Cases 1, 3 and 4 exhibited full-scale tonic-clonic seizures, while case 2 displayed myoclonic and typical absence seizures. Furthermore, case 2 demonstrated delayed growth and development compared to age-matched peers. No abnormality was detected in the head magnetic resonance imaging (MRI). Genetic analysis revealed novel heterozygous variants in the CSNK2B gene in all four cases, including c.175 + 1G > A, c.73-2A > G, c.291 + 1G > A and c.481delA. In case 2, reverse transcription analysis of CSNK2B mRNA revealed the retention of the 3' end sequence of Intron 2 and deletion of the 5' end sequence of Exon 3. In treatment, four case received a combination of one to three types of antiseizure medication and rehabilitation training individually. Case 1 continued to experience seizures to varying degrees, while cases 2-4 demonstrated effective seizure control. Overall motor and intellectual development improved in all four cases, however, there was slow recovery in language function. This study elucidates the molecular etiology of epilepsy in four cases with POBINDS and expands the mutational spectrum of pathogenic variants in the CSNK2B, highlighting their impact on splicing. The highly genetic heterogeneous phenotype of POBINDS relies on the detection of pathogenic variants in CSNK2B. Conventional antiseizure medication effectively control seizures, while rehabilitation treatment can significantly improve intelligence and motor function to varying degrees; however, language recovery tends to be relatively slow.

Poirier-Bienvenu neurodevelopmental syndrome (POBINDS) is a rare neurodevelopmental syndrome, resulting from germline heterozygous CSNKB2 pathogenic variants. The main presentations are severe epilepsy, delayed psychomotor development, and/or profound intellectual disability. More recently, CSNK2B pathogenic variants have been reported in patients with mild intellectual disability and no history of epileptic symptoms. Short stature is present in 66% of patients, in half of these cases due to proven growth hormone deficiency. Whole genome sequencing (WGS) was performed through a French genomic program for a patient with isolated growth hormone deficiency after negative next generation sequencing (NGS) results. NGS panel analysis of CSNK2B and genes involved in isolated growth hormone deficiency (IGHD) was performed in 44 patients from the Genhypopit network (n = 2144) with growth hormone deficiency (GHD) and intellectual disability (ID) or epilepsy and in a convenience cohort of 68 GHD patients. We present the first case of POBINDS presenting mainly as growth delay due to GHD. Genome analysis revealed a de novo pathogenic variant in the translation initiation codon of CSNK2B (c.1 A > G, p.(Met1?)). The patient had mild intellectual disability and subsequent analysis of the patient's clinical history revealed that he had had febrile convulsions, compatible with POBINDS. No CSNK2B pathogenic variants were identified among the 44 selected patients with GHD and ID or epilepsy, or in a convenience cohort of 68 patients with GHD. Although rare, pediatricians should be aware that POIBNDS syndrome may present as IGHD with mild ID.

Seizures have been identified in most patients with CSNK2B-related Poirer-Bienvenu Neurodevelopment syndrome (POBINDS). Detailed descriptions of seizure phenotypes, various genotypes, and long-term follow-up visits are required for clinicians to provide reasonable clinical management for such patients. We report two new Chinese patients with varying sizes of 6p21.33 deletions encompassing the CSNK2B gene who presented with intellectual disability and seizures. Furthermore, we conducted a literature review of previously reported patients with 6p21.33 deletions or CSNK2B variants. We summarized and analyzed the clinical characteristics of these patients with seizures. The occurrence of a biphasic pattern of epilepsy and pharmacoresistant epilepsy in patients with CSNK2B variants is severely underestimated. One of our patients underwent a long follow-up period and presented with comprehensive disease progression. Our data suggest that the CSNK2B variant or 6p21.33 deletion should be considered in patients with intellectual disability and epilepsy, especially those characterized by biphasic patterns and digital anomalies. CSNK2B-related neurodevelopmental disorder (CSNK2B-NDD), reported in more than 80 individuals to date, is characterized in most individuals by developmental delay (DD) / intellectual disability (ID) and seizures. Most young children have delays in speech and motor development. The majority of individuals older than age five years at the time of evaluation have ID ranging from borderline/mild to severe/profound. Seizures, present in most individuals, range in type and severity. While many individuals have pharmaco-responsive epilepsy, others have severe epilepsy with recurrent episodes of refractory status epilepticus. Less consistent findings include ataxia or impaired coordination, generalized hypotonia of infancy, neurobehavioral/psychiatric manifestations, and digital anomalies. The diagnosis of CSNK2B-NDD is established in a proband with suggestive findings and a heterozygous CSNK2B pathogenic variant identified by molecular genetic testing. Treatment of manifestations: Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This includes multidisciplinary care by specialists in pediatrics, developmental pediatrics, neurology, physical medicine and rehabilitation, physical therapy, occupational therapy, speech therapy, social work, and medical genetics / genetic counseling. Surveillance: To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, routinely scheduled evaluations with multidisciplinary care providers are recommended. CSNK2B-NDD is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Almost all probands reported to date whose parents have undergone molecular genetic testing have the disorder as the result of a de novo pathogenic variant. Rarely, individuals diagnosed with CSNK2B-NDD have an affected parent. The risk to the sibs of the proband depends on the genetic status of the proband's parents: if a parent of the proband is known to have the CSNK2B pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Once the CSNK2B pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.