This career development award details a 5-year training plan to facilitate transition to an independent career as a hepatogeneticist focused on gene discovery and characterization for hepatobiliary disease. I completed my Pediatrics residency at St. Christopher’s Hospital for Children and my fellowship in Human Genetics at The Children’s Hospital of Philadelphia (CHOP). I am currently an attending physician and research fellow at CHOP in the Division Of Human Genetics. My clinical and research efforts focus on children with hepatobiliary disease. My goals for this proposal are to become more experienced with exome and genetic variant interpretation and to gain experience using zebrafish as a model to study hepatobiliary disease. I will also use this opportunity to develop my ability to design experiments, write successful grant applications, and lead a laboratory, to facilitate a smooth transition to academic faculty. My mentor for this proposal is Dr. Hakon Hakonarson, a Professor of Pediatrics and director of the Center for Applied Genomics (CAG) at CHOP. Dr. Hakonarson has mentored dozens of post-doctoral research fellows and K-awardees, and was the recipient of CHOP’s Research Mentor Award. I will be co-mentored by Dr. Michael Pack, a Professor of Medicine at the University of Pennsylvania (UPenn). Dr. Pack also has an extensive history of mentoring trainees and K-awardees and works closely with Dr. Hakonarson on novel gene characterization. I have also assembled a scientific advisory committee, consisting of Drs. Klaus Kaestner, Ben Stanger, Kirk Wangensteen, Tom Jongens, and Elizabeth Rand, all experts in the fields of hepatology, neurogenetics or genetics with extensive mentoring experience. I will also have the benefit of the outstanding resources at both CHOP and UPenn, which have facilitated career development for countless past trainees. My proposed research focusses on the discovery and characterization of novel genes implicated in hepatobiliary disease. We are assembling a cohort of individuals with unexplained hepatobiliary disease, and will apply a research pipeline to facilitate identification of novel genes. Our laboratory has already identified de novo nonsense and frameshift variants in MED12 as causal for Hardikar Syndrome, a syndromic form of biliary dysgenesis, of previously unknown genetic basis. Aim 1 of this proposal delineates how a patient cohort will be assembled and characterized, and Aim 2 details the characterization of the role of MED12 in biliary development. Completion of the proposed studies will improve our ability to genetically diagnose hepatobiliary disease, better characterize the genetic landscape of these poorly-understood conditions, and elucidate the mechanism by which nonsense and frameshift MED12 variants cause biliary disease. This proposal will also provide me with experience studying hepatobiliary disease in animal and cellular models, writing grants and scientific papers, and allow me to observe h...