...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>PLoS Genetics >Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes
【24h】

Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes

机译：优化孕前载体筛选中隐性遗传状况的临床外显子组设计和并行基因测试：来自14,125个外显子组的转化研究基因组数据

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Limited translational genomic research data have been reported on the application of exome sequencing and parallel gene testing for preconception carrier screening (PCS). Here, we present individual-level data from a large PCS program in which exome sequencing was routinely performed on either gamete donors (5,845) or infertile patients (8,280) undergoing in vitro fertilization (IVF) treatment without any known family history of inheritable genetic conditions. Individual-level data on pathogenic variants were used to define conditions for PCS based on criteria for severity, penetrance, inheritance pattern, and age of onset. Fetal risk was defined based on actual carrier frequency data accounting for the specific inheritance pattern (fetal disease risk, FDR). In addition, large-scale application of exome sequencing for PCS allowed a deep investigation of the incidence of medically actionable secondary findings in this population. Exome sequencing achieved remarkable clinical sensitivity for reproductive risk of highly penetrant childhood-onset disorders (1/337 conceptions) through analysis of 114 selected gene-condition pairs. A significant contribution to fetal disease risk was observed for rare (carrier rate < 1:100) and X-linked conditions (16.7% and 41.2% of total FDR, respectively). Subgroup analysis of 776 IVF couples identified 37 at increased reproductive risk (4.8%; 95% CI = 3.4–6.5). Further, two additional couples had increased risk for very rare conditions when both members of a parental pair were treated as a unit and the search was extended to the entire exome. About 2.3% of participants showed at least one pathogenic variant for genes included in the updated American College of Medical Genetics and Genomics v2.0 list of secondary findings. Gamete donors and IVF couples showed similar carrier burden for both carrier screening and secondary findings, indicating no causal relationship to fertility. These translational research data will facilitate development of more effective PCS strategies that maximize clinical sensitivity with minimal counterproductive effects.
机译：关于外显子组测序和平行基因测试在先孕载体筛选（PCS）中的应用，已经报道了有限的翻译基因组研究数据。在这里，我们提供了来自大型PCS程序的个人水平数据，其中常规进行了配子供体（5,845）或接受体外受精（IVF）治疗的不育患者（8,280）的外显子组测序，而没有任何已知的遗传病史。有关病原体变体的个人水平数据用于根据严重程度，渗透率，遗传模式和发病年龄的标准定义PCS的条件。胎儿风险是根据实际载波频率数据定义的，该频率考虑了特定的遗传模式（胎儿疾病风险，FDR）。此外，PCS外显子组测序的大规模应用允许对该人群中医学上可操作的次要发现的发生率进行深入研究。外显子组测序通过分析114个选定的基因条件对，实现了对高度渗透的儿童期发病的生殖风险（1/337概念）的显着临床敏感性。对于罕见的（携带者比率<1：100）和X连锁疾病（分别占总FDR的16.7％和41.2％），观察到对胎儿疾病风险的重要贡献。对776例IVF夫妇进行的亚组分析确定了37例生殖风险增加（4.8％; 95％CI = 3.4-6.5）。此外，当父母对的两个成员都被视为一个单元并将搜索范围扩展到整个外显子组时，另外两对夫妇的极少数情况风险增加。大约2.3％的参与者显示出至少一种在美国医学遗传学和基因组学v2.0版次要发现结果列表中包含的基因的致病变异。配子供体和IVF对夫妇进行的携带者筛查和第二次发现均显示相似的携带者负担，表明与生育力没有因果关系。这些转化研究数据将有助于开发更有效的PCS策略，从而最大程度地提高临床敏感性，并减少反作用。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号