Functional correlates of clinical phenotype and severity in recurrent SCN2A variants.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
30 05 2022
30 05 2022
Historique:
received:
29
10
2021
accepted:
05
05
2022
entrez:
31
5
2022
pubmed:
1
6
2022
medline:
3
6
2022
Statut:
epublish
Résumé
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 α
Identifiants
pubmed: 35637276
doi: 10.1038/s42003-022-03454-1
pii: 10.1038/s42003-022-03454-1
pmc: PMC9151917
doi:
Substances chimiques
NAV1.2 Voltage-Gated Sodium Channel
0
SCN2A protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
515Informations de copyright
© 2022. The Author(s).
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