Objective: To provide a critical review the state of the art on the search for modifier genes for disease severity of SCA2.

Background: Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder caused by a CAG repeat expansion mutation in the ATXN2 gene. Disease severity is largely determine by the repeat length, tought additional modifier genes have been identified in candidate gene studies.

Method: A critical literature review was conducted. PubMed, EMBASE, SCOPUS, and the Web of Science databases were searched for studies on modifier genes of SCA2 published up to January 2026. Advanced search strategy was used for the selection of articles, taking into account the methodological quality and validity of the studies.

Results: Fifteen original studies on modifier genes of SCA2 were included. These studies are based on the candidate gene approach, most commonly addressing the impact of normal variation in additional CAG repeat containing loci on the age at disease motor onset. There is a lack of replication in most candidate genes studied in SCA2, associated to insufficient statistical power, heterogeneities in phenotype definitions and precision of the genotyping technologies used, sample stratification and unrecognized gene interactions.

Conclusion: The identification of genetic modifiers for disease severity and in SCA2 is a powerful strategy for the elucidation of the underlying mechanisms of disease. However, the lack of replication in most candidate gene studies in SCA2 reinforces the need for genome-wide associaton studies, as an ideal strategy for scaling up the identification of genetic modifiers and empowering the development of targeted and effective therapies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-modifiers-of-the-clinical-phenotype-in-spinocerebellar-ataxia-type-2-25-years-of-candidate-genes-studies-and-the-forthcoming-gwas-era/