Programmpunkt

11:44–11:46

Titel: Poirier-Bienvenu neurodevelopmental syndrome in three brothers due to a pathogenic CSNK2B-variant and paternal germ line mosaicism
ID: P-ClinG-044
Art: Postertalk
Redezeit: 2 min
Session: Poster Session
ClinG 2

Referent: Silja Burkhard (Innsbruck/AT)


Abstract - Text

Abstract-Text

Background: Poirier-Bienvenu syndrome (POBINDS; OMIM# 618732) is a rare, autosomal dominant neurodevelopmental disorder caused by variants in the CSNK2B gene (OMIM *115441). Thus far, less than 40 patients have been described in literature. All of them were simplex cases, the majority with confirmed de novo variants. The phenotypic description within the patient cohorts revealed heterogeneity of the clinical features with an overlap of seizures, mild to severe developmental delay and intellectual disability.


Patients: We report three teenage brothers with global developmental delay (dominantly with speech delay and dyspraxia), intellectual disability, generalized epilepsy (age of onset 6 months – 2 years), autism spectrum disorder, restlessness, short attention span, aggressive behavior, Smith-Magenis-like facial features and obesity. No distinctive brain anomaly or other malformation were detected.


Method: Whole-exome sequencing using the Twist Comprehensive Exome (Twist Bioscience) on the NextSeq2000 sequencing platform (Illumina). Alignment of sequences to the human reference sequence GRCh37 (hg19). Data analysis with SeqNext, varSEAK (JSI medical systems GmbH) and VarSeq (Golden Helix).


Results/Discussion: We identified a novel heterozygous 4 bp frameshift duplication c.583_586dupATGG (p.(Ala196Aspfs*51)) in the C-terminal domain of the CSNK2B gene in all three brothers. This variant was subsequently also identified in the healthy father in a mosaic state (11% of reads [34/303] in DNA from leucocytes). The CSNK2B gene encodes for the regulatory β-subunit of the protein kinase CK2, an ubiquitous serine/threonine kinase predominantly expressed in the brain. The p.(Ala196Aspfs*51) variant alters and elongates the c-terminal protein sequence important for β-subunit dimerization, interaction with the catalytic α-subunits and ultimately protein complex formation. We hypothesize that this frameshift variant interferes with formation of the protein kinase CK2 complex leading to POBINDS in our patients. The father does not show any symptoms related to POBINDS, suggesting that the mosaic CSNK2B variant in his case was not sufficient to cause POBINDS.


Conclusion: The phenotype of the three brothers fits well with the recently described spectrum of Poirier-Bienvenu neurodevelopmental syndrome. This is the first report of a familial case of POBINDS due to parental germ line mosaicism.


 


Keywords: CSNK2B, Protein kinase CK2, Casein 2 kinase, Poirier-Bienvenu syndrome, POBINDS, epilepsy, ID, developmental delay, germ line mosaicism