CSNK2B – Poirier-Bienvenu Neurodevelopmental Syndrome

Poirier-Bienvenu neurodevelopmental syndrome (POBINDS) is an autosomal dominant disorder caused by heterozygous variants in CSNK2B, characterized by early‐onset epilepsy, global developmental delay, hypotonia, and facial dysmorphism. Clinical validity is rated as Definitive based on more than 60 unrelated probands with de novo variants, segregation in familial cases, and concordant functional studies demonstrating a consistent disease mechanism.

Genetic Evidence

Inheritance is autosomal dominant with predominantly de novo heterozygous CSNK2B variants. Over 60 unrelated probands have been reported with POBINDS ([PMID:36833176]). Segregation analysis includes two affected relatives with inherited pathogenic variants ([PMID:37717460]). The variant spectrum comprises truncating alleles (22 nonsense or frameshift variants) confirmed in multiple cohorts ([PMID:35774559]), 18 missense substitutions enriched in the zinc‐finger domain ([PMID:40317201]), and 14 splice‐site mutations demonstrated to abrogate normal splicing ([PMID:35774559]). Notable recurrent alleles include start‐codon losses (c.1A>G) and hotspot missense changes (e.g., p.Cys137Phe).

A representative pathogenic variant is c.453_c.454insAC (p.His152fsTer76) identified in a Chinese family by trio exome sequencing and validated by Sanger analysis ([PMID:38037515]).

Functional Evidence

Pathogenic CSNK2B variants cause loss of CK2β function via haploinsufficiency. Splicing assays (minigene) confirm exon skipping for intronic alleles leading to premature termination ([PMID:35774559]). Western blotting demonstrates reduced CK2β protein for frameshift and nonsense mutations. Structural studies of zinc‐finger missense variants (p.Arg111Pro, p.Cys137Phe) show impaired holoenzyme formation and proteasomal degradation ([PMID:40317201]). Additional work reveals dominant‐negative perturbation of canonical Wnt signaling by specific codon Asp32 variants ([PMID:35571680]).

Conflicting Evidence

Two de novo missense variants at codon Asp32 also segregate with a distinct craniodigital intellectual disability syndrome, suggesting allelic heterogeneity but not refuting the primary CSNK2B–POBINDS association.

Conclusion

Extensive genetic and experimental data firmly establish CSNK2B loss‐of‐function as the cause of POBINDS. Molecular diagnosis enables early clinical intervention, seizure management, and accurate genetic counseling. Key Take-home: Testing for CSNK2B should be included in gene panels for early‐onset epilepsy with developmental delay to guide prognosis and family planning.

References

• Molecular genetics & genomic medicine • 2024 • Genetic analysis and literature review of a Poirier-Bienvenu neurodevelopmental syndrome family line caused by a de novo frameshift variant in CSNK2B. [PMID:38037515]
• Genes • 2023 • Haploinsufficiency as a Foreground Pathomechanism of Poirer-Bienvenu Syndrome and Novel Insights Underlying the Phenotypic Continuum of CSNK2B-Associated Disorders. [PMID:36833176]
• Frontiers in neuroscience • 2022 • Splicing Interruption by Intron Variants in CSNK2B Causes Poirier-Bienvenu Neurodevelopmental Syndrome: A Focus on Genotype-Phenotype Correlations. [PMID:35774559]
• Biological chemistry • 2025 • Pathogenic missense variants of CSNK2B associated with Poirier-Bienvenu neurodevelopmental disorder impact differently on CK2 holoenzyme formation. [PMID:40317201]
• Epilepsy & behavior: E&B • 2023 • Refining of the electroclinical phenotype in familial and sporadic cases of CSNK2B-related Neurodevelopmental Syndrome. [PMID:37717460]
• HGG advances • 2022 • De novo variants of CSNK2B cause a new intellectual disability-craniodigital syndrome by disrupting the canonical Wnt signaling pathway. [PMID:35571680]

Evidence Based Scoring (AI generated)