Genotype-informed clinical subtyping and treatment landscape of CSNK2B-related Poirier-Bienvenu neurodevelopmental syndrome

Abstract Background CSNK2B -related Poirier-Bienvenu neurodevelopmental syndrome (POBINDS) is characterised by heterogeneous seizure phenotypes and treatment courses. We integrated five newly identified Chinese patients with an updated patient-level literature dataset to delineate clinically interpretable seizure patterns, genotype-informed variant groups, and treatment outcomes. Methods We combined five newly identified Chinese patients with published patient-level cases from an updated systematic review. The five local children underwent clinical assessment, trio-based sequencing, and Sanger validation. Published and local cases were harmonised at the patient level and grouped aspredicted loss-of-function variants and splice-site or splice-region variants (pLoF/splice), zinc-finger missense, non-zinc-finger missense, or unresolved variants. We performed descriptive and exploratory subgroup analyses and an HPO-based unsupervised clustering analysis to identify recurrent clinical constellations. Results The combined cohort comprised 117 patients, including 112 literature-derived cases and five local patients. Epilepsy was reported in 116/117 patients, and seizure onset occurred within the first year in 78/108 evaluable patients. Generalized tonic-clonic seizures (67/115) and focal seizures (32/115) were the most frequent classifiable seizure types. pLoF/splice accounted for 77/117 patients and non-zinc-finger missense variants for 29/117. Exploratory HPO-based clustering of 115 patients identified four clinical profiles. Age at seizure onset differed overall ( P = 0.010; FDR q = 0.039); the myoclonic-atonic profile had later onset than the focal-predominant and tonic-clonic-predominant profiles (pairwise FDR q = 0.032 for both). Variant-group composition did not differ across profiles. Of 93 patients with outcome data, 61 had controlled seizures, 2 were partially controlled, and 30 remained uncontrolled. Valproate and levetiracetam were the most frequently reported antiseizure medications. Conclusions CSNK2B -related POBINDS is characterized by early-onset epilepsy, which presents with a broad spectrum of seizure types and developmental variability. While genotype-informed grouping aids in organizing this heterogeneity, it does not fully predict treatment responses. This limitation underscores the necessity for longitudinal multicenter data to inform precision counseling and management strategies.