Comprehensive and non-invasive prenatal screening of coding variation

摘要 无创产前筛查(Nips)包括评估循环中的无细胞胎儿dna(Cffdna)。 从母体血浆中提取的染色体及其在临床上的广泛应用 怀孕期间的非整倍体现在是例行公事，也是护理的标准。而NIPS技术已经发展到 检测一些靶向基因组异常，目前的方法分辨率低，只能捕获 对产前诊断很重要的一小部分遗传疾病。我们对6个样品的初步研究 提出了一种高分辨率无创产前筛查(HrNIPS)的可行性，它可以捕捉到 大多数致病基因编码变异(SNV、INDELL、CNV)。然而，我们的结果表明，调用 所有类型的变异都可以通过校准统计模型和开发新的 技巧。表型数据的整合将允许对已识别的病原菌进行解释和优先排序 变种。 因此，我们将在100个具有配对胎儿外显子组测序数据的样本上部署hrNIPS，以开发和 在如此大量的样本上校准方法(目标1)。方法调用这些示例的Variation。 改进了方法，并实现了一个基础设施，以使用 表观方案(目标2)。此外，我们将使用表现包和相关的HPO术语来利用 表型感知算法，以确定识别的变异的优先顺序，以供进一步审查。我们将在一个 使用ACMG标准的临床背景，并探索哪些类型的变异可能影响产前护理(目标3)。 最后，我们将研究hrNIPS作为母体携带者筛查的潜在附加值。与这些同时进行的 研究目标，一个由七名导师和顾问组成的非凡团队，涵盖学科、职业阶段和 各机构将提供教学培训、实践研究支持和定期的演讲机会。 总而言之，使用hrNIPS全面评估怀孕期间的编码变异的能力将使早期 和用于分子诊断的无创妊娠评估，并有可能改变标准 关爱。

Abstract Non-invasive prenatal screening (NIPS) involves assessment of circulating cell-free fetal DNA (cffDNA) extracted from maternal plasma and the widespread clinical application of this technique to detect chromosomal aneuploidies in pregnancy is now routine and the standard of care. While NIPS technology has advanced to detect some targeted genomic abnormalities, current approaches are low-resolution and able to capture only a small fraction of genetic conditions important to prenatal diagnosis. Our preliminary studies on 6 samples suggest the feasibility of a high resolution non-invasive prenatal screen (hrNIPS), that can capture the vast majority of pathogenic coding variation (SNV, indel, CNV). However, our results suggest that the ability to call all types of variation can be improved through calibration of statistical models and development of new techniques. Integration of phenotype data will allow interpretation and prioritization of identified pathogenic variants. Therefore, we will deploy hrNIPS on 100 samples with paired fetal exome sequencing data to develop and calibrate methods over this large number of samples (Aim 1). We will call variation on these samples using the improved methods and implement an infrastructure to capture systematic phenotypes in these samples using the phenopackets schema (Aim 2). Further, we will use phenopackets and associated HPO terms to leverage phenotype-aware algorithms to prioritize identified variants for further review. We will interpret all variation in a clinical context using ACMG criteria and explore which types of variants might impact prenatal care (Aim 3). Finally, we will investigate the potential added value of hrNIPS as a maternal carrier screen. In parallel with these research aims, an exceptional team of seven mentors and advisors across disciplines, career stages, and institutions will provide didactic training, hands-on research support, and regular opportunities for presentation. Collectively, the ability to comprehensively assess coding variation in pregnancy with hrNIPS would allow early and non-invasive pregnancy assessment for molecular diagnosis and has the potential to transform the standard of care.