Movement disorders : official journal of the Movement Disorder Society · 2026
Frequency of ZFHX3-Mediated Spinocerebellar Ataxia 4 in a US Undiagnosed Ataxia Cohort.
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Chen Annie, Avadhani Udbhav, Ngo Kathie, Corona Rosario I, Neto George de V Carvalho, Figueroa Karla P, Undiagnosed Diseases Network, Perlman Susan, Pulst Stefan M, Nelson Stanley F, Wong Darice, Fogel Brent L
Аннотация
BACKGROUND: Spinocerebellar ataxia 4 (SCA4) is a late-onset dominant ataxia with neuropathy caused by exonic GGC repeat expansion in the ZFHX3 gene thought to originate from a Swedish founder event. The GC-rich expansion is highly thermodynamically stable, posing challenges for standard clinical genetic testing methods. Development of a high-throughput relatively inexpensive detection method would benefit both clinical diagnostic testing and large-scale research applications.
OBJECTIVE: Using a cost-effective high-throughput polymerase chain reaction (PCR) assay, we assessed the frequency of SCA4 repeat expansion in an undiagnosed US ataxia cohort.
METHOD: Primers flanking the ZFHX3 repeat region were used under optimized PCR conditions to assess for expanded GGC repeats in 687 undiagnosed ataxia patients. Repeat size was determined by fragment analysis and orthogonally confirmed with long-read sequencing (Oxford Nanopore Technologies).
RESULTS: We identified pathogenic SCA4 expansions in three families with cerebellar ataxia and sensory/autonomic neuropathy. The pathogenic alleles were confirmed to be of Swedish ancestry using comprehensive haplotype analysis of 14 single nucleotide polymorphisms (SNPs) previously associated with ZFHX3 expansion. Two families carried all 14 SNPs, suggesting this may represent an ancestral haplotype. Utilizing a minimal haplotype present in all reported patients, we bioinformatically assessed 852 additional subjects, for a total of 1539 screened, but did not identify additional SCA4 patients.
CONCLUSION: Using a high-throughput cost-effective PCR assay, we identified three SCA4 families in a large US ataxia cohort. Haplotype analysis supports a common Swedish founder allele, consistent with previously reported SCA4 cases. SCA4 diagnostic testing is recommended for all patients of Swedish ancestry with undiagnosed ataxia. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
OBJECTIVE: Using a cost-effective high-throughput polymerase chain reaction (PCR) assay, we assessed the frequency of SCA4 repeat expansion in an undiagnosed US ataxia cohort.
METHOD: Primers flanking the ZFHX3 repeat region were used under optimized PCR conditions to assess for expanded GGC repeats in 687 undiagnosed ataxia patients. Repeat size was determined by fragment analysis and orthogonally confirmed with long-read sequencing (Oxford Nanopore Technologies).
RESULTS: We identified pathogenic SCA4 expansions in three families with cerebellar ataxia and sensory/autonomic neuropathy. The pathogenic alleles were confirmed to be of Swedish ancestry using comprehensive haplotype analysis of 14 single nucleotide polymorphisms (SNPs) previously associated with ZFHX3 expansion. Two families carried all 14 SNPs, suggesting this may represent an ancestral haplotype. Utilizing a minimal haplotype present in all reported patients, we bioinformatically assessed 852 additional subjects, for a total of 1539 screened, but did not identify additional SCA4 patients.
CONCLUSION: Using a high-throughput cost-effective PCR assay, we identified three SCA4 families in a large US ataxia cohort. Haplotype analysis supports a common Swedish founder allele, consistent with previously reported SCA4 cases. SCA4 diagnostic testing is recommended for all patients of Swedish ancestry with undiagnosed ataxia. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.