背景:通过体外受精(IVF)产生的胚胎的遗传组成可以通过植入前遗传测试(PGT)进行检查。直到最近,PGT仅限于检测单基因,高风险致病变种,大型结构变体,和非整倍体。最近的进展使IVF胚胎的全基因组基因分型变得可行和负担得起,提高了筛查胚胎患乳腺癌等多基因疾病风险的可能性,高血压,糖尿病,或精神分裂症。尽管围绕这项新技术展开了激烈的争论,称为多基因胚胎筛查(PES;也称为PGT-P),它已经在一些国家提供给IVF患者。几篇文章研究了流行病学,临床,和对PES的伦理观点;然而,一个全面的,缺乏对这一新兴领域的原则性审查。
目的:这篇综述有四个主要目标。首先,鉴于PES研究的跨学科性质,我们的目标是为对该主题感兴趣的生殖专家提供有关PES的独立教育背景。第二,我们对支持和反对引入PES的论点进行了全面和批判性的审查,将关键问题具体化和优先排序。我们还涵盖了IVF患者的态度,临床医生,和公众对PES。第三,我们区分了未来可能的PES患者组,强调与每个群体有关的好处和危害。最后,我们的审查,由ESHRE支持,旨在帮助医疗保健专业人员和政策制定者做出关于是否在诊所引入PES的决策,如果是这样,如何,和谁。
方法:我们使用术语“多基因胚胎筛查”搜索了2003年1月1日至2024年1月3日之间发表的PubMed索引文章,\'多基因植入前\',和“PGT-P”。我们将评论限于英语的主要研究论文,其主要重点是针对医疗状况的PES。我们还包括没有出现在搜索中但被认为是相关的论文。
结果:PES的主要理论益处是降低筛查后出生的儿童的终生多基因疾病风险。风险降低的幅度是根据统计模型预测的,模拟,和兄弟姐妹对分析。基于所有方法的结果表明,在最佳情况下,一种或多种疾病的相对风险降低是可能的。然而,由于这些模型抽象了几个实际限制,实现的收益可能会更小,特别是由于胚胎数量有限和未来风险估计的准确性不清楚.PES可能会对患者及其未来的孩子产生负面影响,以及社会。主要的个人危害是未经指示的IVF治疗,试管婴儿成功率可能会降低,和病人的困惑,不完整的咨询,选择过载。可能的主要社会危害包括丢弃的胚胎,对“设计婴儿”的需求不断增加,过分强调疾病的遗传决定因素,不平等的访问,非欧洲祖先的人的效用较低。益处和危害在主要潜在患者群体中有所不同,包括已经需要IVF的患者,有严重多基因疾病史的有生育能力的人,和肥沃健康的人。在美国,IVF患者和公众对PES的态度似乎是积极的,虽然医疗保健专业人员很谨慎,对临床效用持怀疑态度,关心病人的咨询。
结论:PES降低多种多基因疾病风险的理论潜力需要进一步研究其益处和危害。鉴于大量的实际限制和可能的危害,特别是不必要的IVF治疗和丢弃的存活胚胎,在进一步澄清其利弊平衡之前,应仅在研究背景下提供PES。医疗保健专业人员和公众之间的态度差距需要通过扩大公众和患者的教育,并提供信息和公正的遗传咨询资源来缩小。
BACKGROUND: The genetic composition of embryos generated by in vitro fertilization (IVF) can be examined with preimplantation genetic testing (PGT). Until recently, PGT was limited to detecting single-gene, high-risk pathogenic variants, large structural variants, and aneuploidy. Recent advances have made genome-wide genotyping of IVF embryos feasible and affordable, raising the possibility of screening embryos for their risk of polygenic diseases such as breast cancer, hypertension, diabetes, or schizophrenia. Despite a heated debate around this new technology, called polygenic embryo screening (PES; also PGT-P), it is already available to IVF patients in some countries. Several articles have studied epidemiological, clinical, and ethical perspectives on PES; however, a comprehensive, principled review of this emerging field is missing.
OBJECTIVE: This review has four main goals. First, given the interdisciplinary nature of PES studies, we aim to provide a self-contained educational background about PES to reproductive specialists interested in the subject. Second, we provide a comprehensive and critical review of arguments for and against the introduction of PES, crystallizing and prioritizing the key issues. We also cover the attitudes of IVF patients, clinicians, and the public towards PES. Third, we distinguish between possible future groups of PES patients, highlighting the benefits and harms pertaining to each group. Finally, our review, which is supported by ESHRE, is intended to aid healthcare professionals and policymakers in decision-making regarding whether to introduce PES in the clinic, and if so, how, and to whom.
METHODS: We searched for PubMed-indexed articles published between 1/1/2003 and 1/3/2024 using the terms \'polygenic embryo screening\', \'polygenic preimplantation\', and \'PGT-P\'. We limited the review to primary research papers in English whose main focus was PES for medical conditions. We also included papers that did not appear in the search but were deemed relevant.
RESULTS: The main theoretical benefit of PES is a reduction in lifetime polygenic disease risk for children born after screening. The magnitude of the risk reduction has been predicted based on statistical modelling, simulations, and sibling pair analyses. Results based on all methods suggest that under the best-case scenario, large relative risk reductions are possible for one or more diseases. However, as these models abstract several practical limitations, the realized benefits may be smaller, particularly due to a limited number of embryos and unclear future accuracy of the risk estimates. PES may negatively impact patients and their future children, as well as society. The main personal harms are an unindicated IVF treatment, a possible reduction in IVF success rates, and patient confusion, incomplete counselling, and choice overload. The main possible societal harms include discarded embryos, an increasing demand for \'designer babies\', overemphasis of the genetic determinants of disease, unequal access, and lower utility in people of non-European ancestries. Benefits and harms will vary across the main potential patient groups, comprising patients already requiring IVF, fertile people with a history of a severe polygenic disease, and fertile healthy people. In the United States, the attitudes of IVF patients and the public towards PES seem positive, while healthcare professionals are cautious, sceptical about clinical utility, and concerned about patient counselling.
CONCLUSIONS: The theoretical potential of PES to reduce risk across multiple polygenic diseases requires further research into its benefits and harms. Given the large number of practical limitations and possible harms, particularly unnecessary IVF treatments and discarded viable embryos, PES should be offered only within a research context before further clarity is achieved regarding its balance of benefits and harms. The gap in attitudes between healthcare professionals and the public needs to be narrowed by expanding public and patient education and providing resources for informative and unbiased genetic counselling.