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.

KCNT2-Related Disorders: Phenotypes, Functional, and Pharmacological Properties / Cioclu, M. C.; Mosca, I.; Ambrosino, P.; Puzo, D.; Bayat, A.; Wortmann, S. B.; Koch, J.; Strehlow, V.; Shirai, K.; Matsumoto, N.; Sanders, S. J.; Michaud, V.; Legendre, M.; Riva, A.; Striano, P.; Muhle, H.; Pendziwiat, M.; Lesca, G.; Mangano, G. D.; Nardello, R.; Servettini, I.; Belperio, G.; Kamsteeg, E. -J.; Takahashi, K.; Mitsuhashi, S.; Palmer, E. E.; Bye, A. M.; Madrigal, I.; Alvarez-Mora, M. I.; Sanchez, A.; Meletti, S.; Helbig, I.; Le Tanno, P.; Gerard, B.; El Chehadeh, S.; Lemke, J. R.; Moller, R. S.; Soldovieri, M. V.; Rubboli, G.; Taglialatela, M.. - In: ANNALS OF NEUROLOGY. - ISSN 0364-5134. - 94:2(2023), pp. 332-349. [10.1002/ana.26662]

KCNT2-Related Disorders: Phenotypes, Functional, and Pharmacological Properties

Meletti S.;
2023

Abstract

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.
2023
94
2
332
349
KCNT2-Related Disorders: Phenotypes, Functional, and Pharmacological Properties / Cioclu, M. C.; Mosca, I.; Ambrosino, P.; Puzo, D.; Bayat, A.; Wortmann, S. B.; Koch, J.; Strehlow, V.; Shirai, K.; Matsumoto, N.; Sanders, S. J.; Michaud, V.; Legendre, M.; Riva, A.; Striano, P.; Muhle, H.; Pendziwiat, M.; Lesca, G.; Mangano, G. D.; Nardello, R.; Servettini, I.; Belperio, G.; Kamsteeg, E. -J.; Takahashi, K.; Mitsuhashi, S.; Palmer, E. E.; Bye, A. M.; Madrigal, I.; Alvarez-Mora, M. I.; Sanchez, A.; Meletti, S.; Helbig, I.; Le Tanno, P.; Gerard, B.; El Chehadeh, S.; Lemke, J. R.; Moller, R. S.; Soldovieri, M. V.; Rubboli, G.; Taglialatela, M.. - In: ANNALS OF NEUROLOGY. - ISSN 0364-5134. - 94:2(2023), pp. 332-349. [10.1002/ana.26662]
Cioclu, M. C.; Mosca, I.; Ambrosino, P.; Puzo, D.; Bayat, A.; Wortmann, S. B.; Koch, J.; Strehlow, V.; Shirai, K.; Matsumoto, N.; Sanders, S. J.; Michaud, V.; Legendre, M.; Riva, A.; Striano, P.; Muhle, H.; Pendziwiat, M.; Lesca, G.; Mangano, G. D.; Nardello, R.; Servettini, I.; Belperio, G.; Kamsteeg, E. -J.; Takahashi, K.; Mitsuhashi, S.; Palmer, E. E.; Bye, A. M.; Madrigal, I.; Alvarez-Mora, M. I.; Sanchez, A.; Meletti, S.; Helbig, I.; Le Tanno, P.; Gerard, B.; El Chehadeh, S.; Lemke, J. R.; Moller, R. S.; Soldovieri, M. V.; Rubboli, G.; Taglialatela, M.
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