Objective:

To report a novel KIF1A variant in a 57-year-old woman and explore its association with cerebellar atrophy and ataxia, highlighting the significance of evaluating variants outside the typical motor domain in diagnosing KIF1A-associated neurological disorders (KAND).

Background:

KIF1A mutations are linked to neurological disorders, including hereditary spastic paraplegia and cerebellar ataxia, with most pathogenic variants located in the motor domain. This report examines a variant outside this region to expand understanding of KIF1A-related conditions.

Design/Methods:

We present a case of a 57-year-old woman with a history of dysarthria, gait imbalance, and cerebellar atrophy. Genetic testing using next-generation sequencing (NGS) identified a novel KIF1A variant, c.1788_1790delinsACG (p.His596_Pro597delinsGlnArg), which was not found in major population databases. We also reviewed the patient’s family history and performed segregation analysis to explore the inheritance of this variant, as similar symptoms were observed in her mother and maternal brother.

Results:

The KIF1A variant, located outside the motor domain, was classified as a variant of uncertain significance (VUS). It was absent from large population databases, and in silico analyses suggested a potentially detrimental effect on the protein. The presence of the same variant in the patient’s mother and maternal brother, who exhibit similar clinical features, suggests a possible familial association. The patient’s clinical presentation, including dysarthria, ataxia, and cerebellar atrophy, aligns with KIF1A-related disorders but occurred later in life compared to typical cases.

Conclusions:

This case introduces a novel KIF1A variant outside the motor domain and highlights the importance of considering less common variants when diagnosing KIF1A-associated neurological disorders. The familial pattern observed underscores the value of family history in genetic diagnosis. Comprehensive genetic testing and family screening are crucial for understanding the full spectrum of KIF1A-related conditions. Further studies are needed to understand the variant's impact on KIF1A function and its clinical significance.