AbstractCurrently, a prognostic biomarker-based model is being developed to predict the onset and disease progression of Huntington’s Disease (HD) and Spinocerebellar Ataxia (SCA) types 1 and 3, both late-onset genetic neurodegenerative diseases lacking a disease-modifying treatment (DMT). The need for more accurate predictions of onset and disease progression arises in the context of clinical trials evaluating the effectiveness of potential DMTs and identifying the optimal time to initiate such a DMT.

摘要目前，正在开发一种基于预后生物标志物的模型来预测亨廷顿舞蹈病（HD）和脊髓小脑共济失调（SCA）1型和3型的发病和疾病进展，这两种迟发性遗传性神经退行性疾病都缺乏疾病改善治疗（DMT）。在评估潜在DMT有效性并确定启动此类DMT的最佳时间的临床试验中，需要更准确地预测发病和疾病进展。

Moreover, such a prognostic model may provide mutation carriers with personal utility. The aim of this article is to anticipate the ethical issues raised by these new prognostic models and to formulate the ethical issues that need to be addressed to facilitate an ethically responsible development and implementation of such a model.

此外，这种预后模型可以为突变携带者提供个人效用。本文的目的是预测这些新的预后模型提出的道德问题，并制定需要解决的道德问题，以促进这种模型的道德负责任的开发和实施。

Part one of this article describes the ethical issues raised by presymptomatic genetic testing for HD and evaluates whether and how these issues may also occur by predicting onset and disease progression. Part two presents the results of a critical interpretative review into the ethical issues raised by biomarker testing in other late-onset neurodegenerative diseases lacking a DMT.

本文的第一部分描述了HD症状前基因检测引起的伦理问题，并通过预测发病和疾病进展来评估这些问题是否以及如何发生。第二部分介绍了对缺乏DMT的其他迟发性神经退行性疾病中生物标志物检测引起的伦理问题进行批判性解释性审查的结果。

The review aims to identify new ethical issues related to biomarker testing for predicting the onset and disease progression of HD and SCA. Finally, based on parts one and two, part three proposes a research agenda for the near future regarding the most pressing ethical issues that need to be addressed to ensure an ethically responsible implementation of such a prognostic model in both research settings and clinical practice..

该评价旨在确定与生物标志物测试相关的新伦理问题，以预测HD和SCA的发病和疾病进展。最后，在第一部分和第二部分的基础上，第三部分提出了近期的研究议程，涉及需要解决的最紧迫的伦理问题，以确保在研究环境和临床实践中以伦理责任的方式实施这种预后模型。。

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Fig. 1Fig. 2: Adapted PRISMA flow diagram.

图1图。2： 改编的PRISMA流程图。

NotesPersonal utility is the degree to which a (biomarker) test has ‘the potential to effect change on a (non-medical) personal level’ [3]. Examples include life and family planning, financial affairs, and advanced care planning.Some at-risk individuals might be more receptive to presymptomatic genetic testing if more accurate AO&POD information were available.

注：个人效用是（生物标志物）测试“有可能影响（非医学）个人水平的变化”的程度。例子包括生活和计划生育、财务和高级护理计划。如果有更准确的AO和POD信息，一些高危人群可能更容易接受症状前基因检测。

However, whether this is the case is currently unknown.There are two types of reproductive genetic testing. In prenatal diagnosis, the embryo’s mutation carrier status is tested in utero after natural conception. In preimplantation genetic testing, embryos created through in vitro fertilisation are screened, and only those that do not carry the mutation are selected for implantation.In non-disclosure testing, medical professionals become aware of the prospective parent’s carrier status, but the carrier status is not communicated to the prospective parent.

然而，目前尚不清楚情况是否如此。生殖基因检测有两种类型。在产前诊断中，胚胎的突变携带者状态在自然受孕后在子宫内进行测试。在植入前基因测试中，筛选通过体外受精产生的胚胎，仅选择不携带突变的胚胎进行植入。在保密测试中，医疗专业人员会意识到准父母的携带者身份，但携带者身份不会传达给准父母。

In exclusion testing, embryos not carrying the allele of the prospective grandparent with the mutation are selected. Both prospective parent and medical professionals remain unaware of the prospective parent’s carrier status.One such initiative is the Genetic Discrimination Observatory, founded in 2018.

在排除测试中，选择不携带具有突变的预期祖父母等位基因的胚胎。准父母和医疗专业人员都不知道准父母的携带者身份。其中一个倡议是2018年成立的基因歧视观察站。

This international network researches genetic discrimination and aims to provide policy guidance on a (inter)national level [37].While most papers focus on the research setting, the distinction between research setting and clinical practice is not always clearly defined [38].For example, in the United States, privacy protection laws do not extend to the retrieval of biomarker tests such as amyloid [70] by insurance companies and employers.For example, informing asymptomatic individuals of an increased risk of AD may lead to decreased performance on memory tests [.

该国际网络研究遗传歧视，旨在（国际）国家层面提供政策指导。虽然大多数论文都集中在研究环境上，但研究环境和临床实践之间的区别并不总是明确的（38）。。例如，告知无症状个体AD风险增加可能导致记忆测试表现下降[。

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Download referencesAcknowledgementsWe would like to thank several researchers from the CureQ consortium for explaining their specific tasks and activities within the CureQ project to us, as well as for providing feedback on a draft version of this manuscript, in particular prof. dr. H.H.

下载参考文献致谢我们要感谢CureQ联盟的几位研究人员向我们解释了他们在CureQ项目中的具体任务和活动，并就本手稿的草稿提供了反馈，特别是H.H.教授。

Kampinga and prof. dr. E.A. Reits.FundingThis study is part of the research project ‘CureQ - Predict, Delay, and Cure polyglutamine(Q) caused neurodegeneration’. This research project is funded by NWO, the Dutch Research Council (project number NWA.1389.20.244).Author informationAuthors and AffiliationsDept.

Kampinga和E.A.Reits教授。资助这项研究是“CureQ-预测，延迟和治愈聚谷氨酰胺（Q）引起的神经变性”研究项目的一部分。该研究项目由荷兰研究委员会NWO资助（项目编号NWA.1389.20.244）。作者信息作者和附属机构。

of Medical Ethics, Philosophy, and History of Medicine, Erasmus Medical Centre, Rotterdam, The NetherlandsMax Rensink, Ineke Bolt & Maartje SchermerAuthorsMax RensinkView author publicationsYou can also search for this author in.

医学伦理学，哲学和医学史，鹿特丹伊拉斯谟医学中心，荷兰伦辛，Ineke Bolt＆Maartje SchermerAuthorsMax RensinkView作者出版物您也可以在中搜索这位作者。

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& Schermer, M. Predicting age of onset and progression of disease in late-onset genetic neurodegenerative diseases: An ethics review and research agenda..

&Schermer，M。预测迟发性遗传性神经退行性疾病的发病年龄和疾病进展：伦理审查和研究议程。。

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