Truncating Variants in KIF5C Cause a Milder Disorder Distinct From KIF5C-Associated Cortical Dysplasia

Distinct, recurrent missense variants in KIF5C have previously been described in a small number of patients with cortical dysplasia and severe intellectual disability. We aimed to further characterize the phenotype associated with KIF5C variants, including truncating variants.

We analyzed ten newly identified individuals with disease-associated KIF5C variants and compared them to previously reported cases. The variant spectrum was evaluated in a multicenter case series, and a cross-sectional analysis of the phenotypic range was performed. Molecular modeling was used to identify variant clusters and to provide insights into their potential functional effects.

In our cohort of 19 individuals (ten newly and nine previously reported), we identified eight distinct variants: three truncating, four missense, and one in-frame deletion. Individuals with missense variants consistently exhibited severe developmental delay, absence of speech, seizures, and malformations of cortical development. In contrast, individuals with truncating variants showed milder developmental delay, less severe speech impairment, and no malformations of cortical development.

Our findings suggest a genotype-phenotype correlation in KIF5C, with truncating variants associated with a milder phenotype compared to missense variants.