Key result
Pathogenic KCNT2 variants were associated with intellectual disability (21/22) and epilepsy (15/25), and exhibited gain-of-function (8) or loss-of-function (6) in vitro phenotypes.
Observational (n=25)
Yes
Pathogenic KCNT2 variants cause distinct gain- or loss-of-function phenotypes with unique pharmacological profiles, highlighting the potential for targeted therapies based on molecular phenotype.
May guide variant interpretation in DEE; extends KCNT2 spectrum with functional data but leaves targeted therapies open.
OBJECTIVE: Pathogenic variants in KCNT2 are rare causes of developmental epileptic encephalopathy (DEE). We herein describe the phenotypic and genetic features of patients with KCNT2-related DEE, and the in vitro functional and pharmacological properties of KCNT2 channels carrying 14 novel or previously untested variants. METHODS: Twenty-five patients harboring KCNT2 variants were investigated: 12 were identified through an international collaborative network, 13 were retrieved from the literature. Clinical data were collected and included in a standardized phenotyping sheet. Novel variants were detected using exome sequencing and classified using ACMG criteria. Functional and pharmacological studies were performed by whole-cell electrophysiology in HEK-293 and SH-SY5Y cells. RESULTS: The phenotypic spectrum encompassed: (a) intellectual disability/developmental delay (21/22 individuals with available information), ranging from mild to severe/profound; (b) epilepsy (15/25); (c) neurological impairment, with altered muscle tone (14/22); (d) dysmorphisms (13/20). Nineteen pathogenic KCNT2 variants were found (9 new, 10 reported previously): 16 missense, 1 in-frame deletion of a single amino acid, 1 nonsense, and 1 frameshift. Among tested variants, 8 showed gain-of-function (GoF), and 6 loss-of-function (LoF) features when expressed heterologously in vitro. Quinidine and fluoxetine blocked all GoF variants, whereas loxapine and riluzole activated some LoF variants while blocking others. INTERPRETATION: We expanded the phenotypic and genotypic spectrum of KCNT2-related disorders, highlighting novel genotype-phenotype associations. Pathogenic KCNT2 variants cause GoF or LoF in vitro phenotypes, and each shows a unique pharmacological profile, suggesting the need for in vitro functional and pharmacological investigation to enable targeted therapies based on the molecular phenotype. ANN NEUROL 2023;94:332-349.
No takes yet. Share an insight, caveat, or question.
Cioclu et al. (2023) conducted an observational in KCNT2-related developmental epileptic encephalopathy (DEE) (n=25). Pathogenic KCNT2 variants was evaluated on Phenotypic and genetic features, and in vitro functional properties. Pathogenic KCNT2 variants were associated with intellectual disability (21/22) and epilepsy (15/25), and exhibited gain-of-function (8) or loss-of-function (6) in vitro phenotypes.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: