Genetic Epilepsy

Gene: KCNT2

Green List (high evidence)

Gain of function, loss of function, change of function, and the possibility of a dominant negative mechanism, have all been reported for pathogenic KCNT2 variants in patients with early-onset epileptic encephalopathies, including epilepsy of infancy with migrating focal seizures (PMID: 29069600, PMID: 29740868, PMID: 32038177).

Additional recent publication from 2020 (PMID:32038177) reports two NMD-predicted variants which were shown to result in a loss of protein function in patients with EIMFS. One of the variants was suspected to exert a dominant negative effect. The authors report that "similar phenotypes were observed in patient B carrying the p.L48Qfs43 mutation (∼55% decrease KNa current density) or in a patient carrying the gain of function p.R190P mutation (Ambrosino et al., 2018) suggests that KNa channels efficiency should be tightly regulated during brain development and that any alteration, whatever its direction, would deeply impact on cortical networks activities."

Created: 7 Apr 2020, 1:28 a.m. | Last Modified: 7 Apr 2020, 1:28 a.m.

Panel Version: 0.2033

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Epileptic encephalopathy, early infantile, 57, 617771; Epilepsy of infancy with migrating focal seizures (EIMFS)

Publications

• 29069600
• 29740868
• 32038177

Mode of pathogenicity
Other

Green List (high evidence)

Reviewed by E Palmer: Ambrosino et al described 2 unrelated females with de novo variants in KCNT2. The first patient had the variant p.(Arg190His) had with West syndrome followed by Lennox-Gastaut syndrome , the second patient had the variant p.(Arg190Pro) and DEE with migrating focal seizures. Both variants were absent gnomad and had supportive in silico support for pathogenicity. In an electrophisological model both KCNT2 R190P and KCNT2 R190H increased maximal current density and shifted toward more negative membrane potential values the activation curve of KCNT2 channels, consistent with gain of function effects. PMID: 29740868.

Gururaj et al describe one male with de novo variant in KCNT2 p. (Phe240Leu) and early infantile epileptic encephalopathy. he variant was absent gnomad and supportive evidence of pathogenicity This variant was electrophysiologically modelled and revealed that the variant resulted in a 'change in function' demonstrating unusual altered selectivity in KNa channels.PMID: 29069600.
Sources: Literature

Created: 19 Dec 2019, 6:14 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Epileptic encephalopathy, early infantile, 57, MIM#617771; Developmental and epileptic encephalopathy

Publications

• 29069600
• 29740868

Green List (high evidence)

A.


Ambrosino et al described 2 unrelated females with de novo variants in KCNT2. The first patient had the variant p.(Arg190His) had with West syndrome followed by Lennox-Gastaut syndrome , the second patient had the variant p.(Arg190Pro) and DEE with migrating focal seizures. Both variants were absent gnomad and had supportive in silico support for pathogenicity. In an electrophisological model both KCNT2 R190P and KCNT2 R190H increased maximal current density and shifted toward more negative membrane potential values the activation curve of KCNT2 channels, consistent with gain of function effects. PMID: 29740868.

Gururaj et al describe one male with de novo variant in KCNT2 p. (Phe240Leu) and early infantile epileptic encephalopathy. he variant was absent gnomad and supportive evidence of pathogenicity This variant was electrophysiologically modelled and revealed that the variant resulted in a 'change in function' demonstrating unusual altered selectivity in KNa channels.PMID: 29069600.
Sources: Literature

Created: 19 Dec 2019, 3:37 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Developmental and epileptic encephalopathy

Publications

• (PMID: 29069600
• 29740868)

Mode of pathogenicity
Other