KIF5C-Related Neurodevelopmental Disorder: Three New Cases and Additional Neuroradiologic Insights

Pathogenic variants in KIF5C, encoding a neuronal kinesin motor protein, cause a rare neurodevelopmental disorder characterized by profound global developmental delay/intellectual disability mainly associated with absent speech and severe motor disability, epilepsy, and behavioral problems.

Three individuals with KIF5C variants were evaluated through clinical, neuroimaging, and genetic assessments, and their findings were compared with previously reported cases. A PubMed search using the term "KIF5C″ was performed on March 2, 2025; only English-language articles with detailed clinical descriptions of participants were included.

Two participants carried the recurrent c.709G > A, p.(Glu237Lys) variant, whereas 1 had a novel substitution, c.606C > G, p.(Ser202Arg). All individuals exhibited severe neurodevelopmental impairment. Neuroimaging revealed complex brain malformations, particularly anterior-predominant pachygyria, as well as white matter and cerebellar abnormalities; 1 participant lacked overt cortical malformations.

These findings emphasize that KIF5C-related disorder displays a broader clinical, genetic, and neuroimaging spectrum than previously recognized and may, in some cases, occur without the classic cortical malformations. The presence of white matter and cerebellar involvement suggests that KIF5C variants may disrupt multiple neurodevelopmental processes. Expanding the recognized phenotype will enhance early diagnosis, deepen our understanding of the disease's clinical spectrum, and inform both management strategies and genetic counseling.