Digenic variant interpretation with hypothesis-driven explainable AI Journal Article
| Authors: | De Paoli, F.; Nicora, G.; Berardelli, S.; Gazzo, A.; Bellazzi, R.; Magni, P.; Rizzo, E.; Limongelli, I.; Zucca, S. |
| Article Title: | Digenic variant interpretation with hypothesis-driven explainable AI |
| Abstract: | The digenic inheritance hypothesis holds the potential to enhance diagnostic yield in rare diseases. Computational approaches capable of accurately interpreting and prioritizing digenic combinations of variants based on the proband's phenotypes and family information can provide valuable assistance during the diagnostic process. We developed diVas, a hypothesis-driven machine learning approach that interprets genomic variants across different gene pairs. DiVas demonstrates strong performance in both classifying and prioritizing causative digenic combinations of rare variants within the top positions across 11 cases with the complete list of variants available (73% sensitivity and a median ranking of 3). Furthermore, it achieves a sensitivity of 0.81 when applied to 645 published causative digenic combinations. Additionally, diVas leverages explainable artificial intelligence to elucidate the digenic disease mechanism for predicted positive pairs. © 2025 The Author(s). Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics. |
| Keywords: | adult; gene mutation; major clinical study; phenotype; classification; kidney disease; diagnostic value; cardiovascular disease; benchmarking; eye disease; pathogenicity; computer model; bioinformatics; hearing disorder; hearing impairment; bone disease; cardiomyopathy; rare disease; hypogonadotropic hypogonadism; inheritance; machine learning; long qt syndrome; monogenic disorder; predictive model; human; article; human genetics; ciliopathy; explainable artificial intelligence |
| Journal Title: | NAR Genomics and Bioinformatics |
| Volume: | 7 |
| Issue: | 2 |
| ISSN: | 2631-9268 |
| Publisher: | Oxford University Press |
| Date Published: | 2025-06-01 |
| Start Page: | lqaf029 |
| Language: | English |
| DOI: | 10.1093/nargab/lqaf029 |
| PROVIDER: | scopus |
| PMCID: | PMC11954523 |
| PUBMED: | 40160220 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
