MyOme, Inc., Menlo Park, CA, USA.
Natera, Inc., San Carlos, CA, USA.
Nat Med. 2022 Mar;28(3):513-516. doi: 10.1038/s41591-022-01735-0. Epub 2022 Mar 21.
Preimplantation genetic testing (PGT) of in-vitro-fertilized embryos has been proposed as a method to reduce transmission of common disease; however, more comprehensive embryo genetic assessment, combining the effects of common variants and rare variants, remains unavailable. Here, we used a combination of molecular and statistical techniques to reliably infer inherited genome sequence in 110 embryos and model susceptibility across 12 common conditions. We observed a genotype accuracy of 99.0-99.4% at sites relevant to polygenic risk scoring in cases from day-5 embryo biopsies and 97.2-99.1% in cases from day-3 embryo biopsies. Combining rare variants with polygenic risk score (PRS) magnifies predicted differences across sibling embryos. For example, in a couple with a pathogenic BRCA1 variant, we predicted a 15-fold difference in odds ratio (OR) across siblings when combining versus a 4.5-fold or 3-fold difference with BRCA1 or PRS alone. Our findings may inform the discussion of utility and implementation of genome-based PGT in clinical practice.
胚胎植入前遗传学检测（PGT）已被提议作为一种降低常见疾病传播的方法；然而，更全面的胚胎遗传评估，结合常见变体和罕见变体的影响，仍然不可用。在这里，我们使用分子和统计技术的组合，在 110 个胚胎中可靠地推断出遗传基因组序列，并对 12 种常见疾病的易感性进行建模。我们观察到在 5 天胚胎活检的病例中，与多基因风险评分相关的位点的基因型准确性为 99.0-99.4%，在 3 天胚胎活检的病例中为 97.2-99.1%。将罕见变体与多基因风险评分（PRS）相结合，可以放大同胞胚胎之间的预测差异。例如，在一对携带致病性 BRCA1 变体的夫妇中，当结合使用时，我们预测兄弟姐妹之间的优势比（OR）差异为 15 倍，而单独使用 BRCA1 或 PRS 则为 4.5 倍或 3 倍。我们的研究结果可能为基于基因组的 PGT 在临床实践中的效用和实施的讨论提供信息。
