Using AI to help physicians diagnose rare genetic diseases affecting children

Even with genomic sequencing, many people with rare diseases never receive a clear genetic diagnosis. Roughly half remain undiagnosed after extensive testing and specialist review. Their medical data may contain clues but finding them can require sifting through thousands to millions of possible genetic variants, fragmented clinical records, and rapidly changing scientific literature.

As new gene-disease relationships, case reports, and classification evidence accumulate, unsolved cases can become newly interpretable.

Researchers from Boston Children’s Hospital’s Manton Center for Orphan Disease Research, Harvard University, and OpenAI used the OpenAI o3 Deep Research reasoning model to analyze de-identified clinical and genomic information from 376 previously analyzed cases that remained unsolved. The model surfaced evidence-linked candidate explanations for researchers and clinicians to review. Following expert review, additional testing, and clinical confirmation, physicians established diagnoses in 18 cases—an additional diagnostic yield of 4.8% after earlier analysis by specialists. This study was published on June 18, 2026, in NEJM AI and shows how an AI-assisted research workflow can help experts generate leads when revisiting some of the most difficult cases.

Many of these cases had evaded years of expert analysis. In this study, OpenAI o3 Deep Research helped researchers identify leads that were later assessed through established clinical processes, suggesting that expert-led periodic reanalysis could become more scalable as knowledge evolves. The model did not diagnose any patient or make any clinical decision. It produced evidence-linked hypotheses for specialists to review and, where appropriate, investigate through additional testing and confirm in a clinical laboratory.