Epilepsy care pathway : The Finnish model

Abstract

<p>Heterozygous <em>de novo</em> loss of function variants in the motor domain of <em>KIF5C</em> are associated with a neurodevelopmental disorder characterized by infantile-onset epilepsy, frontal cortical dysplasia, and developmental delays including motor and speech impairments. Previously, only three missense variants in <em>KIF5C</em> were known to be pathogenic. We identified an additional six patients with significant developmental delays with heterozygous <em>de novo</em> variants in the <em>KIF5C</em> gene (Glu237Val, Thr93Ile, Thr93Asn, Ser90del, Lys92Arg, and Glu237Lys), of which four variants have not been reported before. Functional assessment was performed on fluorescently-tagged KIF5C variants expressed in isolated hippocampal neurons. The pathogenic <em>de novo</em> variants displayed significantly reduced motor function compared to the wild-type KIF5C. We conclude that the pathogenic <em>de novo</em> variants presented have decreased motor domain activity and that is likely to be the etiology of the patients' symptoms given the gene's constraint in the population. By adding these patients to the seven patients previously reported, we are able to expand the phenotypic spectrum associated with pathogenic <em>KIF5C</em> variants. Evaluation of the neurodevelopmental phenotype of additional individuals with loss of function variants in <em>KIF5C</em> is indicated to further characterize the spectrum of associated phenotypes.<br></p>