Identification of GGC Repeat Expansions in Among Chilean Movement Disorder Patients.

Background: Hereditary ataxias are genetically diverse, yet up to 75% remain undiagnosed due to technological and financial barriers. A pathogenic GGC repeat expansion was recently linked to spinocerebellar ataxia type 4 (SCA4), characterized by progressive ataxia and sensory neuropathy, with all reported cases in individuals of Northern European ancestry.

Methods: We performed Oxford Nanopore Technologies (ONT) genome long-read sequencing (>115 GB per sample) on a total of 15 individuals from Chile; 14 patients with suspected hereditary movement disorders and one unrelated family member. Variants were identified using PEPPER-Margin-DeepVariant 0.8 (SNVs), Sniffles 2.4 (SVs), and Vamos 2.1.3 (STRs). Ancestry was inferred using GenoTools with reference data from the 1000 Genomes Project, Human Genome Diversity Project, and an Ashkenazi Jewish panel. Haplotype analysis was conducted by phasing SNVs within , and methylation profiling was performed with modbamtools.

Results: We identified GGC repeat expansions (47-55 repeats) in four individuals with progressive ataxia, polyneuropathy, and vermis atrophy. One case presented parkinsonism-ataxia, expanding the phenotype. Longer expansions correlated with earlier onset and greater severity. Hypermethylation was detected on the expanded allele, and haplotype analysis linked ultra-rare variants to distant Swedish ancestry.

Conclusion: This is the first report of SCA4 outside Northern Europe, confirming a shared founder haplotype and expansion instability. The presence of parkinsonism broadens the clinical spectrum. Comprehensive genetic testing across diverse populations is crucial, and long-read sequencing enhances diagnostic yield by detecting repeat expansions and SNVs in a single assay.