A scalable approach for genomic-first rare disorder detection in a healthcare-based population

Beyond commonly screened disorders, genomic-first ascertainment of genetic disorders remains underexplored. We developed a scalable framework for 2,701 additional rare genetic disorders, identifying pathogenic variants in 3.2% of a healthcare-based cohort (n = 218,680). Most lacked a corresponding clinical diagnosis, suggesting under-diagnosis, reduced penetrance, and the value of genomics-first detection.