De novo missense variants in KCNJ4 cause neurodevelopmental disorder with or without seizures

Potassium channels participate in critical biological functions and play crucial roles in the mechanisms of various diseases. Here we describe de novo heterozygous missense variants in KCNJ4 gene as a novel genetic cause of neurodevelopmental disorder with or without seizures. Exome sequencing was performed and the data were analyzed in a cohort of 404 individuals with variable unlesional epilepsy phenotypes in the range from self-limiting familial epilepsies to developmental epileptic encephalopathies and 53 individuals with autism spectrum disorder with or without seizures. Clinical history, development, EEG, and MRI were assessed; seizure types were classified. We report a cohort of six individuals with four de novo heterozygous missense variants (p.Phe32Leu, p.Arg181Gln, p.Glu291Gly, and p.Met299Thr) absent in general population and two de novo variants (p.Pro147Leu, p.Arg205His) with extremely low population frequency in the KCNJ4 gene. All variants are classified as likely pathogenic according to the American College of Medical Genetics and Genomics criteria. All individuals presented with neurodevelopmental disorder including speech impairment and had various seizure types, including focal and generalized seizures. Cognitive outcomes ranged from moderate to profound intellectual disability. The present study provides a comprehensive focus on variant identification and phenotypic spectrum characterization, encompassing a wide array of symptoms, including seizures and cognitive outcomes. Our findings highlight KCNJ4 as a newly identified channelopathy gene implicated in neurodevelopmental disorders that manifest with or without seizures.