Additional observation of a de novo pathogenic variant in KCNT2 leading to epileptic encephalopathy with clinical features of frontal lobe epilepsy

Inuzuka, Luciana Midori; Macedo‐Souza, Lúcia Inês; Della-Ripa, Bruno; Monteiro, Fabíola Paoli; Ramos, Luiza; Kitajima, João Paulo; Garzón, Eliana; Kok, Fernando

doi:10.1016/j.braindev.2020.05.003

Cited by 10 publications

(15 citation statements)

References 7 publications

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“…The p.Phe240 residue is situated in the channel pore helix and the authors concluded that this particular variant causes a “change‐in‐function” by altering a K + channel that is usually upregulated by Cl − to become a Na + channel down‐regulated by Cl − . Inuzuka et al (2020) reported another patient with a de novo p.Thr242Asn variant, which lies in the same transmembrane domain, with a non‐dysmorphic epileptic encephalopathy phenotype (Inuzuka et al, 2020). Alagoz et al (2020) also reported two patients with de novo missense variants (p.Asn182Ile and p.Leu880Met, located in the S4 helical and C‐terminal cytoplasmic domains, respectively) in KCNT2 and epileptic encephalopathy without dysmorphic features.…”

Section: Introductionmentioning

confidence: 99%

Recurrent KCNT2 missense variants affecting p.Arg190 result in a recognizable phenotype

Jackson

Banka

Stewart

et al. 2021

American J of Med Genetics Pt A

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KCNT2 variants resulting in substitutions affecting the Arg190 residue have been shown to cause epileptic encephalopathy and a recognizable facial gestalt. We report two additional individuals with intellectual disability, dysmorphic features, hypertrichosis, macrocephaly and the same de novo KCNT2 missense variants affecting the Arg190 residue as previously described. Notably, neither patient has epilepsy.Homology modeling of these missense variants revealed that they are likely to disrupt the stabilization of a closed channel conformation of KCNT2 resulting in a constitutively open state. This is the first report of pathogenic variants in KCNT2 causing a developmental phenotype without epilepsy.

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Section: Introductionmentioning

confidence: 99%

Recurrent KCNT2 missense variants affecting p.Arg190 result in a recognizable phenotype

Jackson

Banka

Stewart

et al. 2021

American J of Med Genetics Pt A

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“…As a recently discovered gene associated with epilepsy disorders, a total of eight patients bearing five KCNT2 variants had been reported (Gururaj et al, 2017 ; Ambrosino et al, 2018 ; Alagoz et al, 2020 ; Inuzuka et al, 2020 ; Mao et al, 2020 ). The KCNT2 -associated DEEs comprises West syndrome as well as epilepsy of infancy with migrating focal seizures (EIMFS).…”

Section: Discussionmentioning

confidence: 99%

“…They investigated the functional consequence of the two mutations, which showed that both mutations reduced whole-cell potassium current (Mao et al, 2020 ). Subsequently, there were two reports describing three patients with EOEE caused by mutations in KCNT2 without functional analysis (Alagoz et al, 2020 ; Inuzuka et al, 2020 ). Here, our patients showed DEE in common with previous studies.…”

Section: Discussionmentioning

confidence: 99%

“…There is a large phenotypic and genetic heterogeneity and the majority of genetic defects are still unknown. Recently, pathogenic variants in KCNT2 gene that encodes the K Na 1.2 subunit (Slick or Slo2.1) have been identified in eight cases (Gururaj et al, 2017 ; Ambrosino et al, 2018 ; Alagoz et al, 2020 ; Inuzuka et al, 2020 ; Mao et al, 2020 ). The KCNT2 -associated DEEs comprises West syndrome, Lennox-Gastaut syndrome (LGS) as well as epilepsy of infancy with migrating focal seizures (EIMFS).…”

Section: Introductionmentioning

confidence: 99%

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Case Report: Causative De novo Variants of KCNT2 for Developmental and Epileptic Encephalopathy

Gong

Jiao

et al. 2021

Front. Genet.

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Objective:KCNT2 gene mutations had been described to cause developmental and epileptic encephalopathies (DEEs). In this study, we presented the detailed clinical features and genetic analysis of two unrelated patients carrying two de novo variants in KCNT2 and reviewed eight different cases available in publications.Methods: Likely pathogenic variants were identified by whole exome sequencing; clinical data of the patients were retrospectively collected and analyzed.Results: Our two unrelated patients were diagnosed with Ohtahara syndrome followed by infantile spasms (IS) and possibly the epilepsy of infancy with migrating focal seizures (EIMFS), respectively. They both manifested dysmorphic features with hirsute arms, thick hair, prominent eyebrows, long and thick eyelashes, a broad nasal tip, and short and smooth philtrum. In the eight patients reported previously, two was diagnosed with IS carrying a ‘change-of-function' mutation and a gain-of-function mutation, respectively, two with EIMFS-like carrying a gain-of-function mutation and a loss-of-function mutation, respectively, one with EIMFS carrying a loss-of-function mutation, three with DEE without functional analysis. Among them, two patients with gain-of-function mutations both exhibited dysmorphic features and presented epilepsy phenotype, which was similar to our patients.Conclusion: Overall, the most common phenotypes associated with KCNT2 mutation were IS and EIMFS. Epilepsy phenotype associated with gain- and loss-of-function mutations could overlap. Additional KCNT2 cases will help to make genotype-phenotype correlations clearer.

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“…Using NGS platforms, several genes encoding voltage-gated ion channels were defined as being associated with epileptic encephalopathies (EE) and developmental and epileptic encephalopathies (DEE) [76,77]. Inuzuka et al [78] described a patient with an uncommon form of hyperkinetic focal motor seizure in EE carrying a newly discovered variant of KCNT2 which affected the putative pore-forming domain of the protein. A group of diseases characterized by monogenic inheritance and developmental disorders, designated (DEE), is a main beneficiary of NGS [79].…”

Section: Epilepsymentioning

confidence: 99%

Next-Generation Sequencing Technologies and Neurogenetic Diseases

Sun

Shen

Fang

et al. 2021

Life

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Next-generation sequencing (NGS) technology has led to great advances in understanding the causes of Mendelian and complex neurological diseases. Owing to the complexity of genetic diseases, the genetic factors contributing to many rare and common neurological diseases remain poorly understood. Selecting the correct genetic test based on cost-effectiveness, coverage area, and sequencing range can improve diagnosis, treatments, and prevention. Whole-exome sequencing and whole-genome sequencing are suitable methods for finding new mutations, and gene panels are suitable for exploring the roles of specific genes in neurogenetic diseases. Here, we provide an overview of the classifications, applications, advantages, and limitations of NGS in research on neurological diseases. We further provide examples of NGS-based explorations and insights of the genetic causes of neurogenetic diseases, including Charcot–Marie–Tooth disease, spinocerebellar ataxias, epilepsy, and multiple sclerosis. In addition, we focus on issues related to NGS-based analyses, including interpretations of variants of uncertain significance, de novo mutations, congenital genetic diseases with complex phenotypes, and single-molecule real-time approaches.

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Additional observation of a de novo pathogenic variant in KCNT2 leading to epileptic encephalopathy with clinical features of frontal lobe epilepsy

Cited by 10 publications

References 7 publications

Recurrent KCNT2 missense variants affecting p.Arg190 result in a recognizable phenotype

Recurrent KCNT2 missense variants affecting p.Arg190 result in a recognizable phenotype

Case Report: Causative De novo Variants of KCNT2 for Developmental and Epileptic Encephalopathy

Next-Generation Sequencing Technologies and Neurogenetic Diseases

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