Identification of GGC Repeat Expansions in ZFHX3 among Chilean Movement Disorder Patients

Hereditary ataxias are genetically diverse, yet up to 75% remain undiagnosed due to technological and financial barriers. The GGC repeat expansion in ZFHX3, responsible for spinocerebellar ataxia type 4 (SCA4), has only been described in individuals of Northern Europeandescent.

Uncover the genetic etiology of suspected hereditary movement disorders.

We performed Oxford Nanopore long-read genome sequencing on 15 individuals with suspected hereditary movement disorders. Using variant calling and ancestry inference tools.

We identified ZFHX3 GGC expansions (47-55 repeats) in 4 patients with progressive ataxia, polyneuropathy, and vermis atrophy. One presented with rapidly progressive parkinsonism-ataxia, expanding the known phenotype. Longer expansions correlated with earlier onset and severity. All carriers shared single nucleotide variants (SNVs) associated with the Swedish founder haplotype, and methylation analysis confirmed allele-specific hypermethylation.

These represent the first SCA4 cases identified outside Northern Europe. Our findings highlight the value of long-read sequencing in resolving undiagnosed movement disorders. Published 2025. This article is a U.S. Government work and is in the public domain in the USA. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.