biostudies-literatureMoreno-Ruiz NCancer Research UKMedical Research CouncilNational Institute for Health Research (NIHR)Wellcome Trust1439-1443https://www.ebi.ac.uk/biostudies/studies/S-EPMC9712436biostudies-literatureUnknown30(12)An important fraction of patients with rare disorders remains with no clear genetic diagnostic, even after whole-exome or whole-genome sequencing, posing a difficulty in giving adequate treatment and genetic counseling. The analysis of genomic data in rare disorders mostly considers the presence of single gene variants in coding regions that follow a concrete monogenic mode of inheritance. A digenic inheritance, with variants in two functionally-related genes in the same individual, is a plausible alternative that might explain the genetic basis of the disease in some cases. In this case, digenic disease combinations should be absent or underrepresented in healthy individuals. We develop a framework to evaluate the significance of digenic combinations and test its statistical power in diffEuropean journal of human genetics : EJHGAssessing the digenic model in rare disorders using population sequencing data.PMC9712436MR/M009203/1MC_EX_MR/M009203/1MC_PC_14089NF-SI-0512-10113NF-SI-0617-10154Stevens HESavage KCraig CEHFowler TChan GCWilliams ESultana RSmith KRBoissiere JMDaugherty LCTregidgo CPullinger JLopez FJWalsh EMaleady-Crowe FGenomics England Research ConsortiumLahnstein LHubbard TJPArostegui JIWatters SAWelland MJStuckey AElgar GHolman JESieghart AZarowiecki MCaulfield MJHamblin AMueller MOrioli ALaayouni HAmbrose JCScott RHSpooner WMcDonagh EMTucci AMoutsianas LBleda MLeigh SEAPatch CThomas ERABrittain HJones LJMason JArumugam PKasperaviciute DRyten MHackett JMRiesgo-Ferreiro PHenderson SCasals FPereira MBRogers TBoardman-Pretty FPolychronopoulos DBaple ELLawson KKayikci MHalai DThompson SRIbanez KMurugaesu NLeong IUSKousathanas ASmedley DWitkowska KTanguy MFurio-Tari PSmith SCJackson RGiess ARendon AMoreno-Ruiz NSosinsky AFoulger REPerez-Gil DNeed ACSawant KBoustred CRde Burca ALao OSiddiq AOdhams CARahim TDevereau AWood SMfalseAssessing the digenic model in rare disorders using population sequencing data.An important fraction of patients with rare disorders remains with no clear genetic diagnostic, even after whole-exome or whole-genome sequencing, posing a difficulty in giving adequate treatment and genetic counseling. The analysis of genomic data in rare disorders mostly considers the presence of single gene variants in coding regions that follow a concrete monogenic mode of inheritance. A digenic inheritance, with variants in two functionally-related genes in the same individual, is a plausible alternative that might explain the genetic basis of the disease in some cases. In this case, digenic disease combinations should be absent or underrepresented in healthy individuals. We develop a framework to evaluate the significance of digenic combinations and test its statistical power in diff2022-01-01T00:00:00Z2022 Dec2025-04-18T16:56:12.578Z2025-04-07T04:24:34.916ZS-EPMC97124363619243910.1038/s41431-022-01191-x