KCNJ4 variants disrupt inward-rectifier potassium channel function and cause refractory epilepsy

Heterozygous *KCNJ4* (Kir2.3 channel) missense variants with gain- or loss-of-function effects on inward-rectifier potassium current

Trio exome sequencing in four unrelated individuals with refractory epilepsy and neurodevelopmental abnormalities identified four rare heterozygous missense variants in KCNJ4, encoding the Kir2.3 channel, all absent from population databases. The clinical spectrum ranged from isolated epilepsy to severe developmental and epileptic encephalopathy. Electrophysiology in Xenopus oocytes revealed variant-specific effects: Gly136Ser and Glu384Lys increased current (gain of function), whereas Val206Met and Met293Lys reduced it (loss of function), independent of protein expression. These data establish KCNJ4 as a novel epilepsy gene through two opposing mechanisms.

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Establishing KCNJ4 as a novel epileptic channelopathy gene is robust thanks to variant-by-variant electrophysiology. The gain/loss-of-function duality is clinically important because it shapes therapeutic reasoning, as with KCNQ2. The gene is already covered by WES — the challenge will be its functional interpretation, especially as in silico prediction does not distinguish gain from loss of function.