Challenges in providing residual risks in carrier testing.
Challenges in providing residual risks in carrier testing.
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DOI：
10.1002/pd.5975
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发表时间：
2021-08
影响因子：
3
通讯作者：
Risch NJ
中科院分区：
文献类型：
--
作者：
Nussbaum RL;Slotnick RN;Risch NJ
尽管携带者测试呈阴性，但个体仍是隐性遗传病携带者的可能性（称为残留风险）已成为携带者筛查的一部分已有二十多年了。剩余风险的计算方法是从人群中的携带者频率中减去测试检测到的致病变异携带者的频率，该频率是根据疾病的发病率估计的。对许多隐性疾病的发病率（以及因此携带者频率）的估计在不同人群中有所不同，并且对于世界上大多数人口的大型携带者筛查小组中的许多基因来说是不准确的或无法获得的。随着变异的新发现或重新分类，测试检测到的致病变异及其频率也会因群体和时间的推移而有所不同，这需要不断更新当今的残留携带者风险。即使使用在特定群体中获得的准确数据得出残余携带者风险，它也可能不适用于该群体中的许多个体，因为血统错误或未经怀疑的混合。数据缺失或不准确，确定有意义的血统特异性风险并适当应用它们的挑战，以及缺乏影响管理的证据，建议患者建议，尽管携带者筛查可能会漏掉一小部分携带者，但当代携带者筛查的残留风险远低于侵入性产前诊断带来的风险，即使夫妇中的一个成员是携带者，并且没有必要努力提供精确的残留携带者风险。目前还没有关于这里讨论的残余风险计算所涉及的方法和不确定性的公开讨论。关于在基因检测中使用血统的讨论已经有很多，但这篇综述强调了在计算和分配特定疾病位点的血统特异性残余携带者风险时出现的严重问题。该综述提出了以前没有被质疑的问题：提供大多不精确的残余携带者风险是否有临床实用性？关于这个主题已经知道了什么？这项研究增加了什么？
The probability an individual is a carrier for a recessive disorder despite a negative carrier test, referred to as residual risk, has been part of carrier screening for over 2 decades. Residual risks are calculated by subtracting the frequency of carriers of pathogenic variants detected by the test from the carrier frequency in a population, estimated from the incidence of the disease. Estimates of the incidence (and therefore carrier frequency) of many recessive disorders differ among different population groups and are inaccurate or unavailable for many genes on large carrier screening panels for most of the world's populations. The pathogenic variants detected by the test and their frequencies also vary across groups and over time as variants are newly discovered or reclassified, which requires today's residual carrier risks to be continually updated. Even when a residual carrier risk is derived using accurate data obtained in a particular group, it may not apply to many individuals in that group because of misattributed ancestry or unsuspected admixture. Missing or inaccurate data, the challenge of determining meaningful ancestry‐specific risks and applying them appropriately, and a lack of evidence they impact management, suggest that patients be counseled that although carrier screening may miss a small fraction of carriers, residual risks with contemporary carrier screening are well below the risk posed by invasive prenatal diagnosis, even if one member of the couple is a carrier, and that efforts to provide precise residual carrier risks are unnecessary. There has been no published discussion of the methods and uncertainties involved in the calculation of residual risk that are discussed here There has been much discussion of using ancestry in genetic testing but this review highlights the serious problems that arise in calculating and assigning ancestry‐specific residual carrier risks at specific disease loci The review questions what has not been questioned before: Is there clinical utility to providing what are mostly imprecise residual carrier risks What's already known about this topic? What does this study add?
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影响因子：
3.9
作者：
Kosoy, Roman;Nassir, Rami;Tian, Chao;White, Phoebe A.;Butler, Lesley M.;Silva, Gabriel;Kittles, Rick;Alarcon-Riquelme, Marta E.;Gregersen, Peter K.;Belmont, John W.;De La Vega, Francisco M.;Seldin, Michael F.
通讯作者：
Seldin, Michael F.
DOI：
10.1038/s41436-020-0869-3
发表时间：
2020-10
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Kaseniit KE;Haque IS;Goldberg JD;Shulman LP;Muzzey D
通讯作者：
Muzzey D
影响因子：
8.8
作者：
Grody, Wayne W.;Cutting, Garry R.;Desnick, Robert J.
通讯作者：
Desnick, Robert J.
影响因子：
2.8
作者：
Noris, Gino;Santana, Carla;Gomez, Rocio
通讯作者：
Gomez, Rocio
影响因子：
2
作者：
Ross, Lainie Friedman
通讯作者：
Ross, Lainie Friedman