Mutations or variants in the voltage-gated sodium channel SCN2A (NaV1.2) have been associated with various neurodevelopmental disorders. The existing paradigm suggests that gain-of-function (GoF) SCN2A variants lead to neonatal-onset epilepsy, while loss-of-function (LoF) variants are linked to autism spectrum disorder (ASD) and intellectual disability (ID).

In the recent study, Thompson et al. challenge this binary GoF/LoF classification framework and argue that it oversimplifies the diverse functional properties of SCN2A variants. By utilizing the SyncroPatch automated patch-clamp system, the authors evaluated the functional properties of 28 disease-associated variants and revealed that many of these variants exhibit mixed patterns of gain- and loss-of-function that are difficult to classify by a simple binary scheme (for example, depolarizing shifts in activation voltage-dependence combined with slower kinetics of fast inactivation).

These findings (based on data recorded from nearly 6000 individual cells) highlight the need for a more nuanced classification of SCN2A variant dysfunction and suggests that a comprehensive understanding of the functional effects of these variants is necessary for accurately predicting their impact on neuronal physiology and associated clinical phenotypes.

In conclusion, this study underscores the complexity of SCN2A variant-associated neurological disorders and emphasizes the advantages of utilizing advanced experimental techniques, such as automated patch-clamp, to comprehensively assess the functional properties of ion channel variants.

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