PROJECT SUMMARY This is an application for continued support for years 46-50 of a postdoctoral training program in medical genetics based in the Department of Molecular and Human Genetics (DMHG) at Baylor College of Medicine (BCM). The DMHG is a bridging department with major clinical activities and strong programs in basic, translational, and clinical research. It uniquely integrates many of the activities that are traditionally found dispersed through many academic departments and centers at most US academic institutions into a single department at BCM. At our core, the training mission unifies all three domains and the success of this training program over the past five decades reflects that integration. The emphasis of this postdoctoral program is on medical and human genetics and on molecular approaches. There are 90 training faculty, 67 with primary and 23 with secondary appointments in the DMHG (compared with 90 at the last competing renewal submitted in 2017). Our strategic plan has enhanced the training environment including new faculty recruitment, development of new clinical training tracks, formation of a diagnostic laboratory joint venture, development of a virtual platform to facilitate patient engagement in clinical care, education, and research, and establishment of an Office of Community Engagement and Diversity (OCED). However, the core of the DMHG mission remains research spanning all areas of human and model organism genetics with focus on medical genetic practice. Trainees derive mainly from ACGME accredited residency and fellowship programs. The focus of the program is to attract highly qualified ABMGG MD, MD/PhD, and PhD trainees who seek an intensive research experience. In the past four years of this cycle of funding, 82% of 12 month slots were assigned to such trainees. Powerful drivers of training include faculty integration within the DMHG Division of Research affairs including multiple NIH funded centers, clinical implementation of innovative technologies in the genetic diagnostic arena, and integration of these elements into clinical training. Our stellar alumni who now populate our and many other medical genetics programs is evidence of the success of this integrated approach. Major strengths of the training environment include a large clinical genetics component; large, comprehensive, and sophisticated diagnostic laboratories; high national ranking of NIH funding and awards among US genetics departments (1st for over decade); NIH Large Scale Sequencing Center; NIH Intellectual and Developmental Disability Research Center; NIH Center for Mendelian Genomics now GREGoR; NIH Undiagnosed Diseases Network (UDN) Clinical Site (CS), Sequencing Core (SC), and Model Organism Screening Center (MOSC); NIH Knockout Mouse Phenotyping Program (KOMP3), NIH CLINGEN, and NIH Center for Precision Medicine Modeling (CPMM).