Phenotype-first patient matching with SimPheny identifies diagnostic candidates beyond curated gene associations.

ABSTRACT: Diagnostic tools for rare diseases typically rely on curated gene-phenotype associations and static disease models, limiting their effectiveness in cases with atypical presentations or previously uncharacterized disorders. To address these limitations, we present SimPheny, a phenotype-first algorithm for gene prioritization that operates independently of documented gene-phenotype associations. SimPheny identifies phenotypically similar diagnosed patients by comparing an undiagnosed patient's disease presentation to a reference cohort of diagnosed cases, and returns gene hypotheses by matching the undiagnosed patient's candidate gene list to the causative genes of similar patients using a statistical scoring model. Evaluated in diagnosed probands from the Undiagnosed Diseases Network (UDN)

SUBMITTER: Cooperstein IB 

PROVIDER: S-EPMC12870595 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature