Research Overview

Dr. O’Donnell-Luria is dedicated to finding a diagnosis for every individual with rare disease. Despite significant diagnostic advances with exome sequencing, 70% of patients remain undiagnosed after clinical exome sequencing. Through the Center for Mendelian Genomics (CMG) at Broad, she focuses on diagnosing these challenging cases. Through sequencing thousands of individuals with rare disease, she found patterns in the sequence data that become apparent while not apparent in focused studies. Under the mentorship of Daniel MacArthur and Heidi Rehm at the CMG, her team applies novel methods such as RNA-sequencing, multinucleotide variant interpretation, structural variant calling, short tandem repeats, and long-range sequencing to diagnose challenging cases. She is interested in evaluating epigenetic changes in undiagnosed patients as a novel approach to improve diagnosis and the understanding of rare disease pathophysiology. Additionally, she is interested in mechanisms of genomic variation, including how new genes arise de novo in human populations and function in brain and germline.

Laboratory Projects

  1. Center for Mendelian Genomics: An NIH-funded center focused on exome, genome, and RNAsequencing undiagnosed families in collaboration with researchers around the world, including many labs in Boston. The team uses in-house genomic analysis software seqr to empower diagnosis and applies novel methods improve rare disease diagnosis.

  2. EpiChroma Clinic research: By evaluating alterations in the chromatin landscape in patients with mutations in chromatin modifying proteins, we can learn what genes underlie these disorders through epigenetic dysregulation. Characterization of altered chromatin profiles will also help to diagnose additional patients. Finally, a long-term goal is to evaluate the potential for therapeutics for these disorders which are often caused by mutated enzymes. Better understanding of these conditions

About Anne O'Donnell

Dr. Anne O’Donnell-Luria obtained her M.D./Ph.D. degrees from Columbia University Medical Center in New York, NY. She completed a five-year combined Pediatrics-Medical Genetics residency training program and an additional year of clinical training in Medical Biochemical genetics at Boston Children’s Hospital and Harvard Medical School, during which she was awarded the American College of Medical Genetics/Pfizer Translation Genomic Scholar Fellowship. In 2017, she joined the Division where she focuses on patients with Mendelian disorders of epigenetic machinery in the EpiChroma Genetics Clinic and follows patients with inborn errors of metabolism. She is the Associate Director of the Center for Mendelian Genomics at the Broad Institute of MIT and Harvard. She is an expert on how to use reference population data (ExAC/gnomAD) for interpreting genomic variation and is a member of the ClinGen Sequence Variant Interpretation Committee. She sees genetics and metabolism patients in clinic and inpatient consultations, while spending a majority of her time in the laboratory.

Selected Publications

Carlston CM*, O'Donnell-Luria AH*, Underhill HR, Cummings BB, Weisburd B, Minikel EV, Birnbaum DP; Exome Aggregation Consortium., Tvrdik T, MacArthur DG, Mao R. Pathogenic ASXL1 somatic variants in reference databases complicate germline variant interpretation for Bohring-Opitz Syndrome. Hum Mutat. 2017 May; 38(5):517-523. PMID: 28229513.

Lek M, Karczewski KJ*, Minikel EV*, Samocha KE*, Banks E, Fennell T, O'Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, …, Daly MJ, MacArthur DG; Exome Aggregation Consortium. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016 Aug 17;536(7616):285- 91.

Whiffin N*, Minikel E*, Walsh R, O'Donnell-Luria AH, Karczewski K, Ing AY, Barton PJR, Funke B, Cook SA, MacArthur D, Ware JS. Using highresolution variant frequencies to empower clinical genome interpretation. Genet Med. 2017 Oct;19(10):1151-1158. PMID: 28518168.

O'Donnell-Luria AH and Miller DT. A Clinician's perspective on clinical exome sequencing. Hum Genet. 2016 Jun;135(6):643-54.

O'Donnell-Luria AH*, Lin AP*, Merugumala SK, Rohr F, Waisbren SE, Lynch R, Tchekmedyian V, Goldberg AD, Bellinger A, McFaline-Figueroa JR, Simon T, Gershanik EF, Levy BD, Cohen DE, Samuels MA, Berry GT**, Frank NY**. Brain MRS glutamine as a biomarker to guide therapy of hyperammonemic coma. Mol Genet Metab. 2017 May; 121(1):9-15. PMID: 28408159. [Cover article]

Edwards JR*, O'Donnell AH*, Rollins RA, Peckham HE, Lee C, Milekic MH, Chanrion B, Fu Y, Su T, Hibshoosh H, Gingrich JA, Haghighi F, Nutter R, Bestor TH. Chromatin and sequence features that define the fine and gross structure of genomic methylation patterns. Genome Res. 2010; 20:972- 980.

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