Abstract
Background: Poirier-Bienvenu neurodevelopmental syndrome (POBINDS) is a rare autosomal dominant neurologic disorder caused by a heterozygous variant of CSNK2B, which is characterized by early onset epilepsy, hypotonia, varying degrees of intellectual disability (ID), developmental delay (DD), and facial dysmorphism. This study clarifies the molecular diagnosis and causative factors of a Chinese boy with POBINDS.
Methods: The clinical phenotypes and ancillary laboratory tests were collected and analyzed by trio whole exome sequencing (WES) and copy number variant sequencing (CNV-seq) in the follow-up proband's families. The candidate variant was validated by Sanger sequencing and bioinformatics software was used to further explore the effect of the de novo frameshift variant on the protein structure.
Results: The proband carries a de novo frameshift variant c.453_c.454insAC (p.H152fs*76) in CSNK2B. According to the ACMG genetic variant classification criteria and guidelines, the locus is a pathogenic variant (PVS1+PS2+PM2) and the associated disease was POBINDS. Protein structure prediction suggests significant differences in amino acid sequences before and after mutation.
Conclusion: A rare case of POBINDS caused by a novel frameshift variant in CSNK2B was diagnosed. The novel variant extends the variation spectrum of CSNK2B, which provides guidance for early clinical diagnosis, genetic counseling and treatment of this family. A review of the currently reported cases of POBINDS further enriches and summarizes the relationship between genotype and phenotype of POBINDS.
Trivisano M, Dominicis A, Stregapede F, Quintavalle C, Micalizzi A, Cappelletti S, Dentici ML, Sinibaldi L, Calabrese C, Terracciano A, Vigevano F, Novelli A, Specchio N. Refining of the electroclinical phenotype in familial and sporadic cases of CSNK2B-related Neurodevelopmental Syndrome. Epilepsy Behav. 2023 Oct;147:109436. doi: 10.1016/j.yebeh.2023.109436. Epub 2023 Sep 15. PMID: 37717460.
Abstract
CSNK2B encodes a regulatory subunit of casein kinase II, which is highly expressed in the brain. Heterozygous pathogenic variants in CSNK2B are associated with Poirier-Bienvenu neurodevelopmental syndrome (POBINDS) (OMIM #618732), characterized by facial dysmorphisms, seizures, intellectual disability, and behavioral disturbances. We report ten new patients with CSNK2B-related Neurodevelopmental Syndrome associated with heterozygous variants of CSNK2B. In three patients, a pathogenic variant was inherited from an affected parent. We describe both molecular and clinical features, focusing on epileptic and neurodevelopmental phenotypes. The median age at follow-up was 8.5 years (range 21 months-42 years). All patients had epilepsy, with onset at a median age of 10.5 months range 6 days-10 years). Seizures were both focal and generalized and were resistant to anti-seizure medications in two out of ten patients. Six patients had mild to moderate cognitive delays, whereas four patients had no cognitive disability. Although all previously reported patients had a de novo CSNK2B pathogenic variant, here we report, for the first time, two familial cases of CSNK2B-related Neurodevelopmental Syndrome. We confirmed the highly variable expressivity of the disease among both interfamilial and intrafamilial cases. Furthermore, this study provides information about the long-term outcome in adult patients and underlines the importance of detailed family history collection before performing genetic testing in patients with epilepsy and neurodevelopmental disorders.
No comments:
Post a Comment