ArticleGenes2026
Multimodal Sequencing and Reanalysis Approaches to End the Diagnostic Odyssey of Individuals with Suspected Rare Monogenic Diseases.
Article in Genes, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Authors and funding
20 authors.
Funding
Abstract
BACKGROUND/
objectivesGenomic testing has transformed rare-disease diagnostics, yet a substantial proportion of individuals remain without a molecular diagnosis even after short-read exome sequencing (SR-ES) or short-read genome sequencing (SR-GS) and repeated conventional analysis.
methodsTo address this persistent gap, we evaluated a coordinated multimodal reanalysis framework for deeply investigated families with suspected monogenic disease. Six families (20 individuals; 8 affected individuals) that had remained unsolved after prior comprehensive testing were reviewed prospectively in weekly interdisciplinary case conferences over one year. Available data included SR-ES, SR-GS, long-read genome sequencing (LR-GS), RNA-seq, optical genome mapping, mobile-element analysis, and mitochondrial genome analysis. The goal was not to test a single modality in isolation, but to assess whether systematic escalation across complementary assays plus continued reinterpretation could improve case resolution.
resultsThree families (50%) achieved a reportable molecular diagnosis, two (33%) yielded strong candidate findings requiring additional evidence, and one (17%) remained without a definitive new molecular diagnosis, although reinterpretation of a previously identified
conclusionsThis small pilot cohort is not intended to estimate general diagnostic yield, but it demonstrates that a coordinated multimodal framework can reveal different sources of added value, including structural variant discovery, orthogonal functional support, and reinterpretation of existing short-read data as knowledge evolves. These findings underscore that archived short-read exome and genome data can retain substantial diagnostic value years after initial testing, particularly when reanalyzed with updated pipelines, expanded disease gene knowledge, and orthogonal multimodal evidence. Adoption of iterative, team-based multimodal strategies may help resolve the most complex unsolved rare-disease cases.
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