Splicing Interruption by Intron Variants in CSNK2B Causes Poirier–Bienvenu Neurodevelopmental Syndrome: A Focus on Genotype–Phenotype Correlations

Abstract

CSNK2B has recently been identified as the causative gene for Poirier–Bienvenu neurodevelopmental syndrome (POBINDS). POBINDS is a rare neurodevelopmental disorder characterized by early-onset epilepsy, developmental delay, hypotonia, and dysmorphism. Limited by the scarcity of patients, the genotype–phenotype correlations in POBINDS are still unclear. In the present study, we describe the clinical and genetic characteristics of eight individuals with POBINDS, most of whom suffered developmental delay, generalized epilepsy, and hypotonia. Minigene experiments confirmed that two intron variants (c.367+5G>A and c.367+6T>C) resulted in the skipping of exon 5, leading to a premature termination of mRNA transcription. Combining our data with the available literature, the types of POBINDS-causing variants included missense, nonsense, frameshift, and splicing, but the variant types do not reflect the clinical severity. Reduced casein kinase 2 holoenzyme activity may represent a unifying pathogenesis. We also found that individuals with missense variants in the zinc finger domain had manageable seizures (p = 0.009) and milder intellectual disability (p = 0.003) than those with missense variants in other domains of CSNK2B. This is the first study of genotype–phenotype correlations in POBINDS, drawing attention to the pathogenicity of intron variants and expanding the understanding of neurodevelopmental disorders.

Genetic analysis and literature review of a Poirier–Bienvenu neurodevelopmental syndrome family line caused by a de novo frameshift variant in CSNK2B

“…CK2β regulates the substrate specific targeting of the catalytic subunit (Lettieri et al, 2019) and together forms a complete CK2 protein kinase structure (Yang et al, 2021). Zhang et al (2022) and Li et al (2019) suggested that variants in zinc finger structural domain cause a milder POBINDS phenotype and that epilepsy is more easily controlled. In contrast, Ballardin et al (2022) suggested that variants in the zinc finger and/or C-terminal structural domains appear to have a more severe phenotype than variants in the N-terminal region in patients with POBINDS.…”

“…(2017), about 81 cases currently reported (including the present case, searched in PubMed), is a rare autosomal dominant neurological disorder caused by heterozygous variants of CSNK2B . POBINDS mostly characterized by different degrees of early onset epilepsy (including GTC, myoclonic seizures, febrile epilepsy, partial‐onset epilepsy, and so on), ID, DD and hypotonia (Di Stazio et al., 2023; Zhang et al., 2022). Some patients have facial dysmorphism, autistic features, learning disabilities (LD), attention deficits, etc.…”

“…It has been suggested that the phenotypic diversity of POBINDS may be associated with variant types of CSNK2B (Orsini et al., 2022). Different teams (Bonanni et al., 2021; Ernst et al., 2021; Orsini et al., 2022; Yang et al., 2022; Zhang et al., 2022) have studied the genotype and phenotype of reported cases and elucidated the relationship, which has expanded the genotype and phenotype spectrum and laid the foundation for studying the phenotypic heterogeneity of POBINDS.…”

“…Zhang et al. (2022) and Li et al. (2019) suggested that variants in zinc finger structural domain cause a milder POBINDS phenotype and that epilepsy is more easily controlled.…”

“…Poirier-Bienvenu neurodevelopmental syndrome (POBINDS, OMIM #618732) is a rare, autosomal dominant neurologic disorder first reported by Poirier et al (2017), which is caused by a heterozygous variant of CSNK2B (OMIM*115441). The clinical phenotype of POBINDS is diverse, with early onset epilepsy, hypotonia, varying degrees of intellectual disability (ID) and developmental delay (DD) as the main clinical manifestations (Di Stazio et al, 2023;Zhang et al, 2022). In addition, some patients have facial deformities, autism, language, mental, behavioral, and motor disorders features, and a few have other atypical phenotypes.…”