BACKGROUND With the help of ART, an advanced parental age is not considered to be a serious obstacle for reproduction anymore. However, significant health risks for future offspring hide behind the success of reproductive medicine for the treatment of reduced fertility associated with late parenthood. Although an advanced maternal age is a well-known risk factor for poor reproductive outcomes, understanding the impact of an advanced paternal age on offspring is yet to be elucidated. De novo monogenic disorders (MDs) are highly associated with late fatherhood. MDs are one of the major sources of paediatric morbidity and mortality, causing significant socioeconomic and psychological burdens to society. Although individually rare, the combined prevalence of these disorders is as high as that of chromosomal aneuploidies, indicating the increasing need for prenatal screening. With the help of advanced reproductive technologies, families with late paternity have the option of non-invasive prenatal testing (NIPT) for multiple MDs (MD-NIPT), which has a sensitivity and specificity of almost 100%. OBJECTIVE AND RATIONALE The main aims of the current review were to examine the effect of late paternity on the origin and nature of MDs, to highlight the role of NIPT for the detection of a variety of paternal age-associated MDs, to describe clinical experiences and to reflect on the ethical concerns surrounding the topic of late paternity and MD-NIPT. SEARCH METHODS An extensive search of peer-reviewed publications (1980–2021) in English from the PubMed and Google Scholar databases was based on key words in different combinations: late paternity, paternal age, spermatogenesis, selfish spermatogonial selection, paternal age effect, de novo mutations (DNMs), MDs, NIPT, ethics of late fatherhood, prenatal testing and paternal rights. OUTCOMES An advanced paternal age provokes the accumulation of DNMs, which arise in continuously dividing germline cells. A subset of DNMs, owing to their effect on the rat sarcoma virus protein–mitogen-activated protein kinase signalling pathway, becomes beneficial for spermatogonia, causing selfish spermatogonial selection and outgrowth, and in some rare cases may lead to spermatocytic seminoma later in life. In the offspring, these selfish DNMs cause paternal age effect (PAE) disorders with a severe and even life-threatening phenotype. The increasing tendency for late paternity and the subsequent high risk of PAE disorders indicate an increased need for a safe and reliable detection procedure, such as MD-NIPT. The MD-NIPT approach has the capacity to provide safe screening for pregnancies at risk of PAE disorders and MDs, which constitute up to 20% of all pregnancies. The primary risks include pregnancies with a paternal age over 40 years, a previous history of an affected pregnancy/child, and/or congenital anomalies detected by routine ultrasonography. The implementation of NIPT-based screening would support the early diagnosis and management needed in cases of affected pregnancy. However, the benefits of MD-NIPT need to be balanced with the ethical challenges associated with the introduction of such an approach into routine clinical practice, namely concerns regarding reproductive autonomy, informed consent, potential disability discrimination, paternal rights and PAE-associated issues, equity and justice in accessing services, and counselling. WIDER IMPLICATIONS Considering the increasing parental age and risks of MDs, combined NIPT for chromosomal aneuploidies and microdeletion syndromes as well as tests for MDs might become a part of routine pregnancy management in the near future. Moreover, the ethical challenges associated with the introduction of MD-NIPT into routine clinical practice need to be carefully evaluated. Furthermore, more focus and attention should be directed towards the ethics of late paternity, paternal rights and paternal genetic guilt associated with pregnancies affected with PAE MDs.

中文翻译：

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从父亲晚期到单基因疾病的产前筛查：证据和伦理问题

背景技术在艺术的帮助下，父母的高龄不再被认为是生育的严重障碍。然而，在生殖医学成功治疗与晚育相关的生育能力下降的背后，隐藏着对未来后代的重大健康风险。尽管高龄产妇是生殖结果不佳的众所周知的风险因素，但了解高龄父亲对后代的影响仍有待阐明。从头单基因疾病 (MDs) 与晚期父亲高度相关。MDs是儿科发病率和死亡率的主要来源之一，给社会造成重大的社会经济和心理负担。虽然个别罕见，但这些疾病的综合患病率与染色体非整倍体的患病率一样高，表明对产前筛查的需求日益增加。在先进的生殖技术的帮助下，晚期亲子鉴定的家庭可以选择针对多个 MD 的无创产前检测 (NIPT) (MD-NIPT)，其敏感性和特异性几乎为 100%。目的和基本原理 本综述的主要目的是检查晚期亲子关系对 MDs 起源和性质的影响，强调 NIPT 在检测各种父亲年龄相关 MDs 中的作用，描述临床经验和反思围绕晚期亲子关系和 MD-NIPT 主题的伦理问题。搜索方法 从 PubMed 和 Google Scholar 数据库中广泛搜索同行评议的英文出版物（1980-2021 年）是基于不同组合的关键词：晚期父亲、父亲年龄、精子发生、自私的精原细胞选择、父亲年龄效应、从头突变 (DNM)、MDs、NIPT、晚期父亲伦理、产前检查和父亲权利。结果 父亲的高龄引发了 DNM 的积累，DNM 出现在不断分裂的生殖细胞中。DNMs 的一个子集，由于它们对大鼠肉瘤病毒蛋白-丝裂原活化蛋白激酶信号通路的影响，对精原细胞有益，导致自私的精原细胞选择和生长，在一些罕见的情况下，可能会导致晚年的精原细胞瘤。在后代中，这些自私的 DNM 会导致具有严重甚至危及生命的表型的父亲年龄效应 (PAE) 疾病。晚期亲子关系的增加趋势和随后的 PAE 疾病高风险表明对安全可靠的检测程序的需求增加，例如 MD-NIPT。MD-NIPT 方法能够为有 PAE 疾病和 MD 风险的妊娠提供安全筛查，这些疾病占所有妊娠的 20%。主要风险包括父亲年龄超过 40 岁的妊娠、受累妊娠/儿童的既往史和/或常规超声检查发现的先天性异常。实施基于 NIPT 的筛查将支持受影响妊娠病例所需的早期诊断和管理。然而，MD-NIPT 的好处需要与将这种方法引入常规临床实践相关的伦理挑战进行平衡，即对生殖自主权、知情同意、潜在的残疾歧视、父亲权利和 PAE 相关问题、获得服务的公平和正义以及咨询的关注。更广泛的影响考虑到父母年龄的增加和 MD 的风险，结合 NIPT 检测染色体非整倍体和微缺失综合征以及检测 MD 可能在不久的将来成为常规妊娠管理的一部分。此外，需要仔细评估与将 MD-NIPT 引入常规临床实践相关的伦理挑战。此外，应将更多的焦点和注意力集中在与受 PAE MDs 影响的妊娠相关的晚期父亲、父亲权利和父亲遗传内疚的伦理上。父亲权利和 PAE 相关问题、获得服务的公平和正义以及咨询。更广泛的影响考虑到父母年龄的增加和 MD 的风险，结合 NIPT 检测染色体非整倍体和微缺失综合征以及检测 MD 可能在不久的将来成为常规妊娠管理的一部分。此外，需要仔细评估与将 MD-NIPT 引入常规临床实践相关的伦理挑战。此外，应将更多的焦点和注意力集中在与受 PAE MDs 影响的妊娠相关的晚期父亲、父亲权利和父亲遗传内疚的伦理上。父亲权利和 PAE 相关问题、获得服务的公平和正义以及咨询。更广泛的影响考虑到父母年龄的增加和 MD 的风险，结合 NIPT 检测染色体非整倍体和微缺失综合征以及检测 MD 可能在不久的将来成为常规妊娠管理的一部分。此外，需要仔细评估与将 MD-NIPT 引入常规临床实践相关的伦理挑战。此外，应将更多的焦点和注意力集中在与受 PAE MDs 影响的妊娠相关的晚期父亲、父亲权利和父亲遗传内疚的伦理上。结合 NIPT 检测染色体非整倍体和微缺失综合征以及检测 MD 可能在不久的将来成为常规妊娠管理的一部分。此外，需要仔细评估与将 MD-NIPT 引入常规临床实践相关的伦理挑战。此外，应将更多的焦点和注意力集中在与受 PAE MDs 影响的妊娠相关的晚期父亲、父亲权利和父亲遗传内疚的伦理上。结合 NIPT 检测染色体非整倍体和微缺失综合征以及检测 MD 可能在不久的将来成为常规妊娠管理的一部分。此外，需要仔细评估与将 MD-NIPT 引入常规临床实践相关的伦理挑战。此外，应将更多的焦点和注意力集中在与受 PAE MDs 影响的妊娠相关的晚期父亲、父亲权利和父亲遗传内疚的伦理上。