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

{"title":"Intergenerationzal genetic instability and anticipation in spinocerebellar ataxia type 3: The impact of parental gender","authors":"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","doi":"10.1016/j.genrep.2025.102206","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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 <em>t</em>-tests, and non-normally distributed variables with Mann-Whitney <em>U</em> tests. Multifactorial regression analysis was conducted to evaluate the impact of parental gender on offspring delta-expanded CAG repeats and genetic anticipation.</div></div><div><h3>Results</h3><div>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 (<em>t</em> = −4.11, <em>p</em> = 0.001). Parental gender significantly influenced both delta-expCAG (<em>p</em> = 0.012; β = 2.71) and offspring anticipation (<em>p</em> = 0.045; β = 5.67).</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":12673,"journal":{"name":"Gene Reports","volume":"39 ","pages":"Article 102206"},"PeriodicalIF":1.0000,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Gene Reports","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2452014425000792","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}

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.

Abstract Image

查看原文本刊更多论文

脊髓小脑性共济失调3型的代际遗传不稳定性和预期：亲代性别的影响

背景脊髓小脑性共济失调3型（SCA3）是常染色体显性小脑性共济失调最常见的形式。代际遗传不稳定是常染色体显性遗传病的常见现象，包括SCA3、SCA2和亨廷顿病（HD）。父母性别已被证明会影响后代的遗传不稳定性，尽管这在SCA3中仍有争议。方法：我们在2014年至2023年间招募了160名来自OSCCAR的参与者。使用Qiagen的QIAamp试剂盒从血液样本中提取基因组DNA。采用PCR和Sanger测序法测定ATXN3基因中CAG重复数。分类变量采用卡方检验，正态分布变量采用独立样本t检验，非正态分布变量采用Mann-Whitney U检验。采用多因素回归分析评价亲本性别对子代δ扩展CAG重复数和遗传预期的影响。结果160例亲代遗传中，129例出现遗传不稳定，其中膨胀95例，收缩34例。遗传不稳定性在父系传播中（89.87%）明显高于母系传播（71.6%）。子代平均expCAG高于亲代。在40例有病史的患者中，平均年龄为12.95±8.5岁，父系遗传与早期发病相关（t = - 4.11, p = 0.001）。父母性别显著影响delta-expCAG (p = 0.012；β = 2.71)和子代预期(p = 0.045；β = 5.67)。结论SCA3的代际遗传不稳定性较高。亲本性别在决定后代δ - expcag和遗传预期方面起着重要作用，父本遗传表现出更大的不稳定性和更早的发病。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

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.