Whole-exome sequencing (WES) has facilitated the discovery of genetic lesions underlying monogenic disorders. Incomplete penetrance and variable expressivity suggest a contribution of additional genetic lesions to clinical manifestations and outcome. Some monogenic disorders may therefore actually be digenic. However, only a few digenic disorders have been reported, all discovered by candidate gene approaches applied to at least one locus. We propose here a two-locus genome-wide test for detecting digenic inheritance in WES data. This approach uses the gene as the unit of analysis and tests all pairs of genes to detect pairwise gene × gene interactions underlying disease. It is a case-only method, which has several advantages over classic case-control tests, in particular by avoiding recruitment of controls. Our simulation studies based on real WES data identified two major sources of type I error inflation in this case-only test: linkage disequilibrium and population stratification. Both were corrected by specific procedures. Moreover, our case-only approach is more powerful than the corresponding case-control test for detecting digenic interactions in various population stratification scenarios. Finally, we confirmed the potential of our unbiased, genome-wide approach by successfully identifying a previously reported digenic lesion in patients with craniosynostosis. Our case-only test is a powerful and timely tool for detecting digenic inheritance in WES data from patients.

全外显子组测序 (WES) 促进了单基因疾病潜在遗传病变的发现。不完全的外显率和可变的表现力表明额外的遗传病变对临床表现和结果的贡献。因此，一些单基因疾病实际上可能是双基因的。然而，仅报道了少数双基因疾病，所有疾病都是通过应用于至少一个基因座的候选基因方法发现的。我们在这里提出了一个双基因座全基因组测试，用于检测 WES 数据中的双基因遗传。这种方法以基因为分析单位，测试所有基因对，检测疾病背后的成对基因×基因相互作用。这是一种仅限病例的方法，与经典的病例对照试验相比，它有几个优点，特别是通过避免招募对照。我们基于真实 WES 数据的模拟研究在此仅案例测试中确定了 I 类错误膨胀的两个主要来源：连锁不平衡和人口分层。两者都通过特定程序进行了纠正。此外，我们的仅案例方法比相应的案例对照测试更强大，用于检测各种人口分层场景中的双基因相互作用。最后，我们通过成功识别先前报道的颅缝早闭患者的双基因病变，证实了我们无偏见的全基因组方法的潜力。我们的仅病例测试是一种强大而及时的工具，可用于检测患者 WES 数据中的双基因遗传。两者都通过特定程序进行了纠正。此外，我们的仅案例方法比相应的案例对照测试更强大，用于检测各种人口分层场景中的双基因相互作用。最后，我们通过成功识别先前报道的颅缝早闭患者的双基因病变，证实了我们无偏见的全基因组方法的潜力。我们的仅病例测试是一种强大而及时的工具，可用于检测患者 WES 数据中的双基因遗传。两者都通过特定程序进行了纠正。此外，我们的仅案例方法比相应的案例对照测试更强大，用于检测各种人口分层场景中的双基因相互作用。最后，我们通过成功识别先前报道的颅缝早闭患者的双基因病变，证实了我们无偏见的全基因组方法的潜力。我们的仅病例测试是一种强大而及时的工具，可用于检测患者 WES 数据中的双基因遗传。