Rare Missense Variants in KCNJ10 Are Associated with Paroxysmal Kinesigenic Dyskinesia

Background Although the group of paroxysmal kinesigenic dyskinesia (PKD) genes is expanding, the molecular cause remains elusive in more than 50% of cases. Objective The aim is to identify the missing genetic causes of PKD. Methods Phenotypic characterization, whole exome sequencing and association test were performed among 53 PKD cases. Results We identified four causative variants in KCNJ10, already associated with EAST syndrome (epilepsy, cerebellar ataxia, sensorineural hearing impairment and renal tubulopathy). Homozygous p.(Ile209Thr) variant was found in two brothers from a single autosomal recessive PKD family, whereas heterozygous p.(Cys294Tyr) and p.(Thr178Ile) variants were found in six patients from two autosomal dominant PKD families. Heterozygous p.(Arg180His) variant was identified in one additional sporadic PKD case. Compared to the Genome Aggregation Database v2.1.1, our PKD cohort was significantly enriched in both rare heterozygous (odds ratio, 21.6; P = 9.7 × 10−8) and rare homozygous (odds ratio, 2047; P = 1.65 × 10−6) missense variants in KCNJ10. Conclusions We demonstrated that both rare monoallelic and biallelic missense variants in KCNJ10 are associated with PKD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. In this work we aimed to elucidate the missing genetic causes of paroxysmal kinesigenic dyskinesia using exome sequencing. We studied 53 PKD cases and identified four rare missense variant in KCNJ10 in 9 patients, a gene that has been associated with Sesame syndrome. A homodimer of Kir4.1, the protein encoded by KCNJ10, is presented on the graphic. Variants previously reported in Sesame syndrome are in blue, variants reported in this work are in red, and clustered in the cytoplasmic domain.