美国博德研究所Kaitlin E. Samocha小组从大规模外显子组测序数据推断复合杂合性。2023年12月6日，《自然—遗传学》杂志在线发表了这项成果。

研究人员开发了一种策略来推断基因内罕见变异对的阶段，利用在基因组聚集数据库（v2, n=12578个外显子组）中观察到的基因型。该方法估计阶段的准确率为96%，无论是在三人组数据中，还是在孟德尔病症患者和假定的因果复合杂合子变体中。研究人员提供了编码变异的相位估计和反式中罕见变异的每个基因计数的公开资源，这有助于解释隐性疾病背景下罕见的共发生变异。

据悉，当一个基因的两个拷贝都受到破坏性遗传变异的影响时，就会出现隐性疾病。当一个病人在一个基因中携带两个潜在的遗传变异时，准确的诊断需要确定这些变异发生在染色体的不同拷贝上（即反式），而不是发生在同一拷贝上（即顺式）。然而，除了父母检测之外，目前用于确定阶段的方法在临床环境中是有限的。

附：英文原文

Title: 

Author: Guo, Michael H., Francioli, Laurent C., Stenton, Sarah L., Goodrich, Julia K., Watts, Nicholas A., Singer-Berk, Moriel, Groopman, Emily, Darnowsky, Philip W., Solomonson, Matthew, Baxter, Samantha, Tiao, Grace, Neale, Benjamin M., Hirschhorn, Joel N., Rehm, Heidi L., Daly, Mark J., ODonnell-Luria, Anne, Karczewski, Konrad J., MacArthur, Daniel G., Samocha, Kaitlin E.

Issue&Volume: 2023-12-06

Abstract: Recessive diseases arise when both copies of a gene are impacted by a damaging genetic variant. When a patient carries two potentially causal variants in a gene, accurate diagnosis requires determining that these variants occur on different copies of the chromosome (that is, are in trans) rather than on the same copy (that is, in cis). However, current approaches for determining phase, beyond parental testing, are limited in clinical settings. Here we developed a strategy for inferring phase for rare variant pairs within genes, leveraging genotypes observed in the Genome Aggregation Database (v2, n=125,748 exomes). Our approach estimates phase with 96% accuracy, both in trio data and in patients with Mendelian conditions and presumed  heterozygous variants. We provide a public resource of phasing estimates for coding variants and counts per gene of rare variants in trans that can aid interpretation of rare co-occurring variants in the context of recessive disease.

DOI: 10.1038/s41588-023-01608-3

Source: https://www.nature.com/articles/s41588-023-01608-3