Variants of unknown significance (VUS) pose an extensive clinical challenge. Our objective was to explore the diagnostic pipeline from symptom onset to molecular diagnosis in autosomal recessive (Spastic ataxia type 2 [SPAX2], Mendelian Inheritance in Man [MIM] number 611302) caused by a new homozygous variant in the KIF1C gene.

Two unrelated individuals with early-onset spastic ataxia were evaluated for genetic etiology by exome sequencing. Case reports were compiled through a medical chart review. Two cellular models were established to assess variant pathogenicity.

Whole exome sequencing revealed a homozygous variant in KIF1C (NM_006612.6: c.833T > C, p.[Leu278Pro]) in a highly conserved motor domain of the KIF1C protein in both individuals. Two cellular models overexpressing a green fluorescent protein (GFP)-tagged KIF1C harboring the p.Leu278Pro variant demonstrated disrupted protein localization, suggesting an impaired trafficking capacity of the mutant KIF1C. A diagnosis of SPAX2 was established based on the in vitro data. Novel clinical findings associated with this KIF1C variant included retinal dysfunction detected by electroretinogram, hypotonia, and a thin corpus callosum in brain MRI.

Classification of pathogenicity requires extensive multidisciplinary effort, which can be burdensome for affected individuals and families. Like other proteins of the kinesin family, variants in KIF1C may underlie retinal dysfunction.