COBT: a gene-based rare variant burden test for case-only study designs using aggregated genotypes from public reference cohorts

Rare disease gene discovery is limited by small cohorts and the frequent absence of matched controls. We present the Case-Only Burden Test (COBT), a gene-based burden test for case-only designs accounting for multiple variants per individual and additive effects. COBT uses a Poisson model to test for excess variants in a gene relative to expectations from population mutation rates. Simulations show high power and competitive performance versus case-control burden tests. Validation on 1000 Genomes data demonstrated good model fit and low false-positive rates. Applied to 478 ciliopathy patients, COBT re-identified known causal genes and highlighted candidate variants in unsolved cases. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-026-01619-9.