Dataset Information

Functional correlates of clinical phenotype and severity in recurrent SCN2A variants.

ABSTRACT: In SCN2A-related disorders, there is an urgent demand to establish efficient methods for determining the gain- (GoF) or loss-of-function (LoF) character of variants, to identify suitable candidates for precision therapies. Here we classify clinical phenotypes of 179 individuals with 38 recurrent SCN2A variants as early-infantile or later-onset epilepsy, or intellectual disability/autism spectrum disorder (ID/ASD) and assess the functional impact of 13 variants using dynamic action potential clamp (DAPC) and voltage clamp. Results show that 36/38 variants are associated with only one phenotypic group (30 early-infantile, 5 later-onset, 1 ID/ASD). Unexpectedly, we revealed major differences in outcome severity between individuals with the same variant for 40% of early-infantile variants studied. DAPC was superior to voltage clamp in predicting the impact of mutations on neuronal excitability and confirmed GoF produces early-infantile phenotypes and LoF later-onset phenotypes. For one early-infantile variant, the co-expression of the α₁ and β₂ subunits of the Na_v1.2 channel was needed to unveil functional impact, confirming the prediction of 3D molecular modeling. Neither DAPC nor voltage clamp reliably predicted phenotypic severity of early-infantile variants. Genotype, phenotypic group and DAPC are accurate predictors of the biophysical impact of SCN2A variants, but other approaches are needed to predict severity.

SUBMITTER: Berecki G

PROVIDER: S-EPMC9151917 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Functional correlates of clinical phenotype and severity in recurrent SCN2A variants.

Berecki Géza G Howell Katherine B KB Heighway Jacqueline J Olivier Nelson N Rodda Jill J Overmars Isabella I Vlaskamp Danique R M DRM Ware Tyson L TL Ardern-Holmes Simone S Lesca Gaetan G Alber Michael M Veggiotti Pierangelo P Scheffer Ingrid E IE Berkovic Samuel F SF Wolff Markus M Petrou Steven S

Communications biology 20220530 1

In SCN2A-related disorders, there is an urgent demand to establish efficient methods for determining the gain- (GoF) or loss-of-function (LoF) character of variants, to identify suitable candidates for precision therapies. Here we classify clinical phenotypes of 179 individuals with 38 recurrent SCN2A variants as early-infantile or later-onset epilepsy, or intellectual disability/autism spectrum disorder (ID/ASD) and assess the functional impact of 13 variants using dynamic action potential clam ...[more]

PMID: 35637276

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Dataset Information

Functional correlates of clinical phenotype and severity in recurrent SCN2A variants.

Publications

Functional correlates of clinical phenotype and severity in recurrent SCN2A variants.

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