Big Data: Genomic Reference Databases to Empower Mendelian Diagnosis


This presentation will discuss how large scale reference population databases have improved molecular diagnoses and variant interpretation. By evaluating where variation is missing from the general population, candidate disease genes constrained for loss of function and missense variation have been identified. We have developed a frequency filtering approach to determine when a variant is to common in the general population to cause a given disease.

Originally published on August 1, 2019

Lecture Presenter

Anne O’Donnell-Luria, MD, PhD

Anne O’Donnell-Luria, MD, PhD

Associate Director
Center for Mendelian Genomics

Anne O'Donnell-Luria is associate director of the Center for Mendelian Genomics at the Broad Institute of MIT and Harvard. She is interested in using large-scale genomic approaches to increasing the rate of rare disease diagnosis through improving rare variant interpretation and empowering the discovery of novel disease genes. She is particularly interested in how we can leverage massive reference population databases such as ExAC and gnomAD in these efforts. She also studies why only some people with a disease-causing genetic variant will develop symptoms, which is known as incomplete penetrance of genetic conditions.

O’Donnell-Luria is also a practicing clinician who runs a clinic at Boston Children’s Hospital (BCH) focused on evaluating families with epigenomic disorders. Her training was supported by a Pfizer/ACMG Foundation Translational Genomic Scholars Fellowship. Her research has been recognized by the David W. Smith Peter Duncan Award (2015), BCH Alumni Association Trainee Travel Award (2016), and BCH Medical Staff Organization Faculty Innovated Research Award (2017).

Prior to joining the Broad Institute in 2015, O'Donnell-Luria completed her M.D./Ph.D. training at Columbia University Medical Center, where her thesis work was on the role of DNA methylation in the pathophysiology of complex disease, particularly breast cancer and psychiatric disease. This was followed by the Five-Year Boston Children's Hospital and Harvard Medical School Combined Pediatrics-Genetics Residency Program and an additional year of clinical training in medical biochemical genetics. She spent 18 months as a clinical fellow in the MacArthur laboratory at the Broad Institute before taking her current post.


After this presentation, participants will be able to:

  • Integrate the use of reference population databases into the practice of variant interpretation
  • Recognize high quality population variants from common sequencing artifacts by viewing read data supporting reference population variant calls
  • Apply appropriate frequency filters in variant interpretation using frequency filtering approach

Sponsored by:

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