The Emirati Genome Program Enables Population-wide Penetrance Estimation and Novel Discovery for Inherited Retinal Disease

Interpreting rare variants remains a major challenge in genomic medicine, particularly for genetically and phenotypically heterogeneous disorders like inherited retinal diseases (IRDs). We introduce a population-scale framework that unites three unprecedented resources: whole genome data from 504,000 individuals in the Emirati Genome Program (EGP); electronic health record (EHR) data from 426,000 of these participants through phenoEGP, phenotype resource derived from Malaffi; and genetically reconstructed pedigrees, made possible by the rich familial structures within the EGP. Together, these datasets enable real-world penetrance estimation of rare variants at a population scale, stratification of individuals and families by clinical actionability, and the discovery of novel IRD-associated variants. Among 1,879 known variants, we found 96 high or complete penetrance, supporting clinical integration, while 36 showed null penetrance, warranting reclassification. We identified 2,131 asymptomatic individuals and 1,013 families as potential candidates for preventive care. Using phenotype-first familial prioritization, we identified 69 likely pathogenic variants among high-disease-burden families, including a novel biallelic BBS12 variant confirmed through cross-cohort screening. We also identified rare, actionable conditions like undiagnosed CYP27A1-related cerebrotendinous xanthomatosis. Our integrative framework enables early detection of at-risk individuals, informs therapeutic decision-making, and uncovers novel disease loci, underscoring the power of population-scale genomic screening to advance precision medicine in rare diseases and provide a scalable model for other heterogeneous conditions.