Not putting the cart before the horse: the complex social and ethical terrain of prenatal exome sequencing.
Not putting the cart before the horse: the complex social and ethical terrain of prenatal exome sequencing.
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DOI：
10.1038/s41431-022-01225-4
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发表时间：
2023-02
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自2020年以来，英国已通过NHS护理提供产前外显子组测序（PES），用于诊断“可能患有单基因畸形疾病”的胎儿[1]。接受PES的胎儿通常具有通过超声成像识别的异常，在这些情况下，寻求分子诊断以告知妊娠和/或新生儿护理的管理。事实上，在整个地球仪，PES的好处时，除了使用染色体微阵列分析（CMA），已被广泛强调。这些益处不仅包括诊断率，还包括促进有关妊娠中止/继续、早期诊断以及开始症状前治疗的知情决策[2，3]。尽管有这些重要的潜在好处，但是，使用全基因组方法进行产前检测还需要仔细考虑，因为一些伦理问题尚未得到充分探讨[4]。Daum等人“的最新论文，提出了扩大使用PES的胎儿，没有异常已经被确定，换句话说，这表明PES可以有效地作为一个第一层筛选测试。作者声称，即使在没有特定指征的妊娠中，PES也“包括CMA的所有诊断产率，并在相当一部分看似健康的胎儿中提供额外的发现”（第11页）。因此，他们认为PES从靶向诊断领域转移到筛查领域的论点主要是基于诊断产量，以及对CMA单独可能提供“虚假保证”的担忧。他们的论文报告了2017年至2022年间在以色列对482名“结构正常”的胎儿进行的PES。为了确定向父母披露哪些结果，研究小组使用了美国医学遗传学和基因组学学院（ACMG）的致病性和可能致病的变体列表，以及ACMG的次要发现列表[5]。然后，这些列表通过仅包括与“中度”或“重度”条件相关的列表进一步缩小，如Lazarin等人（2014）分类法所确定的[6]。“次要发现”的报告仅限于儿童期发病的患者，但重要的是，仍然包括易感基因。使用该系统，该研究确定了4例具有与“中度”或“重度疾病”相关的致病性或可能致病性变体的胎儿（所有这些胎儿随后均被终止）和2例具有儿童期发病继发性发现的胎儿（均持续至足月）。虽然作者强调了这种方法在促进知情的决策在怀孕（在没有孕前载体筛选）的好处，我们认为，有一些伦理问题值得关注之前，ES可以认真考虑作为一种常规形式的产前筛选的“结构正常”的胎儿。首先，我们认为，作者用来确定哪些变异应该报告给准父母的方法需要更多的思考。几位作者，包括货车Rooijk等人。（2020）认为，“已知致病性”的标签应该非常谨慎地应用于遗传变异，因为许多属于这一类别的变异并不是在每种情况下都有临床影响[7]。虽然货车Rooijk等人尽管该研究是在老年人群中进行的，但在产前背景下考虑这些发现可能很重要，因为评估变异对表型的影响的机会有限。此外，通过PES可识别的许多变体（包括本研究中发现的两种-SPRED 1和FGFR 3）与广泛的疾病相关。
Prenatal exome sequencing (PES) for the diagnosis of foetuses ‘with a likely monogenic malformation disorder’has been available through NHS care in the UK since 2020 [1]. Foetuses undergoing PES typically have anomalies that have been identified through sonographic imagining, and in these instances, a molecular diagnosis is sought to inform management of the pregnancy and/or neonatal care. Indeed, across the globe, the benefits of PES when used in addition to chromosomal microarray analysis (CMA), have been widely emphasised. These benefits not only include diagnostic yields, but also the facilitation of informed decision-making regarding pregnancy dis/continuation, early diagnosis, as well as initiation of pre-symptomatic treatment [2, 3]. Despite these important potential benefits, however, the use of genome-wide approaches to prenatal testing also requires careful consideration given the number of ethical issues that have yet to be adequately explored [4]. Daum et al.’s recent paper, makes the case for expanding the use of PES to foetuses where no anomalies have been previously identifiedin other words, suggesting that PES could be usefully employed as a first-tier screening test. The authors claim that PES, even in pregnancies without a specific indication,‘includes all diagnostic yields of CMA and provides additional findings in a considerable fraction of seemingly healthy foetuses’(p. 11). Their argument for the movement of PES out of the realm of targeted diagnostics into that of screening is therefore based, primarily, on diagnostic yields, and a concern that CMA alone may provide ‘false reassurance’. Their paper reports on PES conducted on 482 ‘structurally normal’foetuses between 2017 and 2022 in Israel. In order to determine which results to disclose to parents, the team used the American College of Medical Genetics and Genomics (ACMG)’s list of pathogenic, and likely pathogenic variants, as well as the ACMG’s list of secondary findings [5]. These lists were then further syphoned down by including only those relating to ‘moderate’or ‘severe’conditions, as determined by Lazarin et al’s (2014) taxonomy [6]. Reporting of ‘secondary findings’ were restricted to those with childhood onset, but, importantly, still including susceptibility genes. Using this system, the study identified four foetuses with pathogenic, or likely pathogenic, variants relating to a ‘moderate’or ‘severe disease’(all of which were subsequently terminated) and two foetuses with childhood onset secondary findings (both continued to term). Although the authors emphasise the benefits of this approach in facilitating informed decision-making in pregnancy (in the absence of pre-conception carrier screening), we believe that there are a number of ethical issues deserving of attention before ES could be seriously considered as a routine form of prenatal screening of ‘structurally normal’foetuses. Firstly, the approach used by the authors to determine which variants should be reported back to would-be parents, we believe, requires more thought. Several authors, including Van Rooijk et al.(2020) have argued that the label ‘known pathogenic’should be applied to genetic variants only very sparingly, given that many that fall into this category do not have a clinical impact in every instance [7]. Whilst van Rooijk et al.’s study was carried out in an older population, the findings may nevertheless be important to consider in the prenatal context where there is limited opportunity to assess the impact of a variant on phenotype. In addition, many variants identifiable through PES (including two found in this study-in SPRED1 and FGFR3) are associated with conditions with wide …
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DOI：
10.3390/diagnostics11020224
发表时间：
2021-02-02
期刊：
Diagnostics (Basel, Switzerland)
影响因子：
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作者：
Guadagnolo D;Mastromoro G;Di Palma F;Pizzuti A;Marchionni E
通讯作者：
Marchionni E
DOI：
10.1038/s41436-020-0900-8
发表时间：
2020-11
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
van Rooij J;Arp P;Broer L;Verlouw J;van Rooij F;Kraaij R;Uitterlinden A;Verkerk AJMH
通讯作者：
Verkerk AJMH
DOI：
10.1016/j.bpg.2014.02.004
发表时间：
2014-04-01
影响因子：
3.2
作者：
Pinxten, Wim;Howard, Heidi Carmen
通讯作者：
Howard, Heidi Carmen
影响因子：
5.2
作者：
Shkedi-Rafid, Shiri;Horton, Rachel;Lucassen, Anneke
通讯作者：
Lucassen, Anneke
DOI：
10.1038/s41431-021-00962-2
发表时间：
2022-03
期刊：
European journal of human genetics : EJHG
影响因子：
--
作者：
Boardman FK;Clark CC
通讯作者：
Clark CC