Intergenerationzal genetic instability and anticipation in spinocerebellar ataxia type 3: The impact of parental gender

Background: Spinocerebellar ataxia type 3 (SCA3) is the most common form of autosomal dominant cerebellar ataxia. Intergenerational genetic instability is a common phenomenon in autosomal dominant genetic disorders, including SCA3, SCA2, and Huntington's disease (HD). Parental gender has been shown to influence genetic instability in offspring, though this remains a point of debate in SCA3. Methods: We enrolled 160 participants from OSCCAR between 2014 and 2023. Genomic DNA was extracted from blood samples using Qiagen's QIAamp kit. The number of CAG repeats in the ATXN3 gene was determined using PCR and Sanger sequencing. We analyzed categorical variables with Chi-square tests, normally distributed variables with independent samples t-tests, and non-normally distributed variables with Mann-Whitney U tests. Multifactorial regression analysis was conducted to evaluate the impact of parental gender on offspring deltaexpanded CAG repeats and genetic anticipation. Results: In 160 parent-offspring transmissions, 129 cases displayed genetic instability, including 95 expansions and 34 contractions. Genetic instability was significantly higher in paternal transmissions (89.87 %) compared to maternal transmissions (71.6 %). The mean expCAG in offspring exceeded that of parents. Among 40 cases with documented anticipation, the mean was 12.95 +/- 8.5 years, with paternal inheritance associated with an earlier onset (t = -4.11, p = 0.001). Parental gender significantly influenced both delta-expCAG (p = 0.012; (3 = 2.71) and offspring anticipation (p = 0.045; (3 = 5.67). Conclusion: Intergenerational genetic instability is highly prevalent in SCA3. Parental gender plays a significant role in determining offspring delta-expCAG and genetic anticipation, with paternal transmission showing greater instability and earlier onset.