Mystery Illnesses: Developing a Path to Caring and Discovery


Rare and undiagnosed diseases are increasingly a recognized priority for health and research. Of the estimated 7000 known rare diseases, only a fraction have their molecular and mechanistic bases delineated. These conditions have a disproportionate impact on families and health care costs. They also represent a unique opportunity for discovery of the biologic bases of disease and potential drug targets. To address these challenges, the University of Utah has developed the Penelope Program, a combined clinical and research program that integrates team-based cognitive expertise with advanced genetic testing to optimize the path to care and discovery. We will describe the program’s approach and results to date, with a focus on the spectrum of rare or new conditions discovered so far, and the implications for clinical management and translational research.

Originally presented on December 21, 2017, in Salt Lake City, Utah.

Lecture Presenters

Rong Mao, MD, FACMG

Rong Mao, MD, FACMG

Professor of Pathology
University of Utah School of Medicine
Section Chief, Molecular Genetics and Genomics
ARUP Laboratories

Dr. Mao is a professor of pathology and co-director of the Clinical Medical Genetics Fellowship Program at the University of Utah School of Medicine. She received her MD from Capital University of Medicine in Beijing, China and her MS in molecular pathology from Beijing Union Medical College. She is board certified by the American Board of Medical Genetics with a subspecialty in clinical molecular genetics, and certified with the New York State Department of Health with a subspecialty in genetic testing. She is also a member of several professional societies, including American College of Medical Genetics and Genomics (ACMGG), Association for Molecular Pathology (AMP) and American Society of Human Genetics (ASHG) and College of American Pathologist (CAP). Her research interests include the genotype-phenotype correlations in inborn errors of metabolism and genetic diseases in the RAS/MAPK pathway, and she is involved with implementing Next-Generation Sequencing (NGS) techniques into molecular diagnostics.

Lorenzo D. Botto, MD

Lorenzo D. Botto, MD

Professor of Pediatrics
University of Utah School of Medicine

Lorenzo Botto, MD, is a professor of Pediatrics at the University of Utah School of Medicine. He trained in Europe and the United States in Pediatrics, Pediatric Cardiology, and Medical Genetics, with further subspecialty training in Biochemical Genetics. He trained in and practiced epidemiology and public health at the US Centers for Disease Control and Prevention (EIS and preventive medicine program) for over a decade.

In the clinic, Dr Botto focuses in particular on three areas: diagnosis and care of people with undiagnosed or rare conditions; skeletal dysplasias (genetic disorders of the bone), inherited metabolic diseases (particularly those that affect the brain, the heart, and the production of energy).


After this presentation, participants will be able to:

  • Describe the University of Utah Penelope Undiagnosed and Disease Program (Penelope Program) and the implications of the findings for clinical management and research.
  • Recognize the power of exome sequencing, new gene discovery, and genotype-phenotype correlation.
  • Describe the challenges of exome sequencing data analysis, determination pathogenicity of rare sequence variant, functional study, and re-analysis.

Sponsored by:

University of Utah School of Medicine, Department of Pathology, and ARUP Laboratories