Anne O'Donnell-Luria
The O’Donnell-Luria laboratory studies how genetic variation contributes to the development of rare disease in humans. While individually rare, these conditions collectively affect ~5% of the population. Half of patients remain undiagnosed after clinical testing (karyotype, microarray, exome) leaving many individuals on a long diagnostic odyssey. Identifying a molecular diagnosis is critical for basic science and clinical reasons: it is an important step towards understanding the genetic control of human phenotypes, and towards optimizing medical management, family planning, and opening opportunities to participate in research.
The O’Donnell-Luria Laboratory aims to understand how genetic variants result in human phenotypes and disorders using a variety of complementary approaches and two large datasets. The first is the Genome Aggregation Database, a control reference database with exome or genome data from >180,000 individuals. The second is the Broad Institute Center for Mendelian Genomics with exome or genome data on >10,000 families with rare disease, the majority of which remain unsolved.
After a negative result from exome sequencing, genome sequencing increases the diagnostic rate by <10% because we do not understand the impact most genomic variation. Much of our analysis strategies focus on gene discovery, as there are still thousands of disease-gene relationships to be discovered. Beyond standard analysis, we use complementary technologies like RNA-seq and proteomics to evaluate the impact of variation on RNA transcripts and proteins. We are using computational approaches to identify functional noncoding variation and digenic inheritance (where variants in two genes in combination cause disease). We are evaluating variants in unannotated small proteins identified experimentally in humans. Finally, since only some of the individuals with a pathogenic variant will actually develop disease, due to incomplete penetrance, we study this phenomenon by focusing on individuals who have incomplete penetrance for a variety of conditions.
Located across the Broad Institute and Boston Children’s Hospital, the O’Donnell-Luria Laboratory builds and applies tools to empower genomics research and contribute to gnomAD dataset and the seqr analysis platform. Beyond diagnosis, we contribute to ClinGen efforts to develop and apply standards for variant and gene classification and for calculating rare disease prevalence.
Dr. Anne O’Donnell-Luria received her undergraduate degree in biological chemistry and mathematics, then completed an MD/PhD program at Columbia University Medical School focusing her thesis research on epigenetics. Anne trained in the Boston Children’s Hospital/Harvard Medical School Combined Residency in Pediatrics and Genetics, followed by a clinical fellowship in Medical Biochemical Genetics. She completed her postdoctoral research fellowship in computational genomics at Massachusetts General Hospital and the Broad Institute. She was appointed as faculty at Boston Children’s Hospital and Harvard Medical School in 2019 and is an associate member of the Analytic and Translational Genomics Unit and Center for Genomic Medicine at MGH. Anne’s lab is funded by the National Institutes of Health, the Mathers Foundation, the Manton Center for Orphan Disease Research, and the Chan Zuckerberg Initiative.
The O’Donnell-Luria Laboratory is a collaborative team seeking to diagnose every patient with rare disease and is open to creative approaches that can be applied to these datasets. We benefit from close interactions with the groups of Heidi Rehm, Michael Talkowski, Kaitlin Samocha, and Monica Wojcik. We welcome BBS rotation students with strong quantitative and programming skills or interests. Joint thesis supervision with an experimentalist is a possibility.