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

IF 1 Q4 GENETICS & HEREDITY

Gene Reports Pub Date : 2025-03-24 DOI:10.1016/j.genrep.2025.102206

Mao-Lin Cui , Hao-Ling Xu , Gui-He Li , Wei Lin , Zhuo-Ying Huang , Bei-Ning Ye , Shi-Rui Gan , Ning Wang , Min-Ting Lin , on behalf of the OSCCAR Investigators

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引用次数: 0

Abstract

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 delta-expanded 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; β = 2.71) and offspring anticipation (p = 0.045; β = 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.

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来源期刊

Gene Reports Biochemistry, Genetics and Molecular Biology-Genetics

CiteScore

3.30

自引率

7.70%

发文量

246

审稿时长

49 days

期刊介绍： Gene Reports publishes papers that focus on the regulation, expression, function and evolution of genes in all biological contexts, including all prokaryotic and eukaryotic organisms, as well as viruses. Gene Reports strives to be a very diverse journal and topics in all fields will be considered for publication. Although not limited to the following, some general topics include: DNA Organization, Replication & Evolution -Focus on genomic DNA (chromosomal organization, comparative genomics, DNA replication, DNA repair, mobile DNA, mitochondrial DNA, chloroplast DNA). Expression & Function - Focus on functional RNAs (microRNAs, tRNAs, rRNAs, mRNA splicing, alternative polyadenylation) Regulation - Focus on processes that mediate gene-read out (epigenetics, chromatin, histone code, transcription, translation, protein degradation). Cell Signaling - Focus on mechanisms that control information flow into the nucleus to control gene expression (kinase and phosphatase pathways controlled by extra-cellular ligands, Wnt, Notch, TGFbeta/BMPs, FGFs, IGFs etc.) Profiling of gene expression and genetic variation - Focus on high throughput approaches (e.g., DeepSeq, ChIP-Seq, Affymetrix microarrays, proteomics) that define gene regulatory circuitry, molecular pathways and protein/protein networks. Genetics - Focus on development in model organisms (e.g., mouse, frog, fruit fly, worm), human genetic variation, population genetics, as well as agricultural and veterinary genetics. Molecular Pathology & Regenerative Medicine - Focus on the deregulation of molecular processes in human diseases and mechanisms supporting regeneration of tissues through pluripotent or multipotent stem cells.