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

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Molecular Biology

Background:

• Recurrent missense variants in KIF5C are linked to cortical dysplasia and severe intellectual disability.
• Previous studies identified a small number of patients with these KIF5C variants.
• The phenotypic spectrum of KIF5C variants, including truncating types, requires further characterization.

Purpose of the Study:

• To further characterize the phenotype associated with KIF5C variants.
• To investigate the impact of both missense and truncating KIF5C variants.
• To establish a genotype-phenotype correlation for KIF5C-related disorders.

Main Methods:

• Analysis of ten new individuals with KIF5C variants, alongside nine previously reported cases.
• Multicenter case series to evaluate the spectrum of KIF5C variants.
• Cross-sectional phenotypic analysis and molecular modeling to understand variant effects.

Main Results:

• Eight distinct KIF5C variants identified in 19 individuals: 3 truncating, 4 missense, 1 in-frame deletion.
• Missense variants correlated with severe developmental delay, absent speech, seizures, and cortical malformations.
• Truncating variants associated with milder developmental delay, less severe speech impairment, and absence of cortical malformations.

Conclusions:

• A genotype-phenotype correlation exists for KIF5C variants.
• Truncating KIF5C variants present a milder clinical phenotype compared to missense variants.
• These findings refine understanding of KIF5C-related neurodevelopmental disorders.