Objective: The aim is to identify the missing genetic causes of Paroxysmal Kinesigenic Dyskinesia (PKD)

Background: Although the group of genes associated with PKD is expanding, the molecular cause remains elusive in more than 50% of cases.

Method: 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.

Conclusion: We demonstrated that both rare monoallelic and biallelic missense variants in KCNJ10 are associated with PKD.

Modelling of KCNJ10-encoded Kir4.1 protein.

References: Thomas Wirth and Emmanuel Roze contributed equally and should be considered as co-first authors.
Aurélie Méneret and Mathieu Anheim contributed equally and should be considered as co-last authors.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/rare-missense-variants-in-kcnj10-are-associated-with-paroxysmal-kinesigenic-dyskinesia/