ArticleAnnals of neurology2023
KCNT2-Related Disorders: Phenotypes, Functional, and Pharmacological Properties.
Article in Annals of neurology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 17 citations in OpenAlex.
- Investigating genetic susceptibility to concussion through rare variants in ion channel and neurotransmission genes.Journal of neurology · 2026Article
- Low diagnostic yield of presurgical genetic testing in adult patients with epilepsy.Epilepsia · 2026Article
- Shared Disease Mechanisms in Neurodevelopmental Disorders: A Cellular and Molecular Biology Perspective.Brain sciences · 2025Review
- Electrophysiological Abnormalities and Pharmacological Corrections of Pathogenic Missense Variants in KCNQ3.Neuroscience bulletin · 2025Article
- Fluoxetine Treatment in Epilepsy of Infancy with Migrating Focal Seizures Due to KCNT1 Variants: An Open Label Study.Annals of neurology · 2025Article
- KCNT1 gene variant-associated epilepsy: genetic insights, functional mechanisms, and emerging therapies.Journal of neurology · 2025Review
- Deregulated ion channels contribute to RHOBTB2-associated developmental and epileptic encephalopathy.Human molecular genetics · 2025Article
- Article
- Editorial: Pathogenic potassium channel variants in neurological disorders: from functional analysis to personalized pharmacological approaches.Frontiers in cellular neuroscience · 2025Article
- Molecular pathogenesis of Alzheimer's disease onset in a mouse model: effects of cannabidiol treatment.Frontiers in neuroscience · 2025Article
- A molecular switch in RCK2 triggers sodium-dependent activation of KBiophysical journal · 2024Article
- KCNT1 Channel Blockers: A Medicinal Chemistry Perspective.Molecules (Basel, Switzerland) · 2024Review
- Article
- Heterozygous loss-of-function variants in DOCK4 cause neurodevelopmental delay and microcephaly.Human genetics · 2024Article
- Identification of a novelFrontiers in genetics · 2024Article
- Case report: Marked electroclinical improvement by fluoxetine treatment in a patient withFrontiers in cellular neuroscience · 2024Article
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Authors and funding
26 authors at 17 institutions in 11 countries.
Funding
Abstract
objectivePathogenic 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.
methodsTwenty-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.
resultsThe 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.
interpretationWe 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.
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