Multi-Omics Characterization of a KIF1C Structural Variant in a Patient with a Complex Movement Disorder Partially Responsive to Deep Brain Stimulation

Biallelic KIF1C variants are associated with a spectrum of neurological phenotypes, including spasticity, cerebellar ataxia, chorea, and dystonia. Most reported patients involve single-nucleotide variants, whereas copy number variants (CNVs) have been described only once in the PubMed-listed literature. The therapeutic potential of deep-brain stimulation (DBS) in KIF1C-related disease has not yet been evaluated. We report a patient presenting with spasticity, ataxia, dystonia, and head tremor, in whom prior exome sequencing was inconclusive. A multi-omics approach was applied, including optical genome mapping (OGM), genome sequencing, and transcriptome sequencing. The clinical effect of DBS was assessed. OGM revealed a homozygous KIF1C Exon 17–18 deletion, retrospectively detectable in exome and genome data but initially missed by sequence analysis. Transcriptome sequencing demonstrated significantly reduced KIF1C expression and absence of normally spliced transcripts around those exons, consistent with a loss-of-function mechanism. DBS led to partial clinical improvement, with notable reduction of dystonia and head tremor. Structural variants may be an underrecognized cause of complex movement disorders involving spasticity, ataxia, and dystonia. Diagnostic methods specifically targeting structural variation, such as OGM or CNV analysis of short-read data, can be essential for diagnosis. Transcriptome data add valuable functional insight. This report also suggests that DBS may offer symptomatic benefit in KIF1C-associated disease, particularly for dystonic signs.