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Spinocerebellar ataxia type 4 (SCA4) is an adult-onset neurodegenerative disorder first described in 1996, characterized by cerebellar ataxia, polyneuropathy, and linkage to chromosome 16q22.1. Despite linkage evidence, the causative mutation remained elusive until recent studies identified a GGC repeat expansion in the ZFHX3 gene (ZFHX3) as the underlying defect for SCA4 (Spinocerebellar ataxia type 4).
In a cohort of three Swedish families with undiagnosed adult-onset ataxia, detailed clinical, neuroimaging, and neuropathological investigations revealed dysautonomia, motor neuron signs, polyneuropathy (HP:0001271), and abnormal eye movements (HP:0000496). Genetic analysis using short-read whole genome sequencing, repeat expansion detection, and long-read sequencing identified a novel polyglycine GGC repeat expansion in the last exon of ZFHX3, c.10519GGC[42-74], segregating with disease and absent in 1,000 controls (3 families; PMCID:38973251) (PMID:38973251).
A subsequent long-read sequencing study of 15 Chilean individuals with suspected hereditary ataxias uncovered ZFHX3 GGC repeat expansions (47–55 repeats) in four unrelated cases presenting progressive cerebellar ataxia (HP:0002073) and sensory neuropathy, including one with parkinsonism-ataxia. Expanded alleles exhibited hypermethylation, and haplotype analysis confirmed a shared distant Swedish founder haplotype (4 cases; PMID:40166539).
Repeat size correlated inversely with age at onset and directly with severity, and evidence of anticipation was observed across generations. These findings establish GGC repeat expansions in ZFHX3 as the causative mutation for SCA4, expanding its phenotypic spectrum to include dysautonomia and neuromuscular involvement.
Inheritance is autosomal dominant with anticipation, supported by segregation of the c.10519GGC[42-74] expansion in three multi-affected families and replication in diverse populations. The variant should be interrogated by long-read sequencing or targeted repeat assays in suspected SCA4 cases.
Gene–Disease AssociationStrongSeven probands across five families; segregation in three multi-affected families; replicated in diverse populations Genetic EvidenceStrongSeven cases, including four unrelated individuals; novel GGC repeat expansions segregating in three families; evidence of anticipation and founder haplotype Functional EvidenceLimitedNeuropathological and neuroimaging studies support neurodegenerative mechanism consistent with human phenotype |