Benchmark of computational methods to detect digenism in sequencing data

Digenic inheritance is characterized by the combined alteration of two different genes leading to a disease. It could explain the etiology of many currently undiagnosed rare diseases. With the advent of next-generation sequencing technologies, the identification of digenic inheritance patterns has become more technically feasible, yet still poses significant challenges without any gold standard method. Here, we present a comprehensive overview of the existing methods developed to detect digenic inheritance in sequencing data and provide a classification in cohort-based and individual-based methods. The latter category of methods appeared the most applicable to rare diseases, especially the ones not needing patient phenotypic description as input. We discuss the availability of the different methods, their output and scalability to inform potential users. Focusing on methods to detect digenic inheritance in the case of very rare or heterogeneous diseases, we propose a benchmark using different real-life scenarios involving known digenic and putative neutral pairs of genes. Among these different methods, DiGePred stood out as the one giving the least number of false positives, ARBOCK as giving the greatest number of true positives, and DIEP as having the best balance between both. By synthesizing the state-of-the-art techniques and providing insights into their practical utility, this benchmark serves as a valuable resource for researchers and clinicians in selecting suitable methodologies for detecting digenic inheritance in a wide range of disorders using sequencing data.