Novel KIF5C Gene Mutation Leading to Frontal Pachygyria: A Rare Case Report and a Review of the Literature

Lissencephaly or smooth brain can be classified based on the site of predominant cortical involvement. Identification of "gene-imaging pattern" associations facilitates specific analysis in some genes. KIF5C, a motor kinesin has been implicated in cortical dysplasia with eight reported cases to date. The Glu237 residue represents a hotspot being substituted in six out of seven patients. A uniform pattern of neuroimaging with a predominant frontal and mesio-frontal pachygyria has been observed in patients with mutations in the hotspot residue. Two different de novo disease-causing variants (nonhotspot mutations) were detected to be causative in the remaining two patients, resulting in posterior predominant pachygyria. This has led to the hypothesis of a mutation-specific imaging pattern, in KIF5C-associated lissencephaly. We hereby present a female with a novel nonhotspot mutation in the KIF5C gene. Using whole exome sequencing, a novel de novo missense mutation c.265T>C (p.Ser89Pro) of KIF5C was identified. Neuroimaging revealed a predominant frontal pachygyria, which is akin to the pattern observed with the Glu237 hotspot residue of KIF5C. We also compared the phenotype between patients with and without involvement of the hotspot residue and were able to show that no major differences exist between both groups. We expand the currently known narrow KIF5C mutation spectrum and challenge the notion of a typical pattern of "mutation-specific" imaging abnormality.