APR 12, 2017 07:30 AM PDT

Keynote Presentation - Variant interpretation in Molecular Diagnostics: Challenges and Knowledge Gaps

C.E. CREDITS: P.A.C.E. CE | Florida CE
  • Chief Medical Officer, Invitae
      Dr. Nussbaum is currently the Chief Medical Officer of Invitae, a genetic information and diagnostic company. From 2006-2015, he was the Holly Smith Professor of Medicine at UCSF, Chief of the Division of Genomic Medicine, director of the Genomic Medicine Initiative at UCSF, and Medical Director of both the Cancer Risk Program at the Helen Diller Family Cancer Center and the UCSF Program in Cardiovascular Genetics, where he continues to see patients as a volunteer clinical faculty member. He came to UCSF in 2006 from the Division of Intramural Research of the National Human Genome Research Institute, NIH, where he served for 12 years as Chief of the Genetic Diseases Research and Inherited Disease Research Branches. Before his time at NIH, he was a faculty member in the Department of Genetics at the University of Pennsylvania and an Attending Physician at Children's Hospital of Philadelphia. He received his training in medicine in the Harvard-MIT Joint Program in Health Technology, his internal medicine training at Barnes Hospital/Washington University, and his genetics training at Baylor College of Medicine. He is board certified in internal medicine, clinical genetics and clinical molecular genetics. Dr. Nussbaum directed the original research that led to the discovery of mutations in -synuclein in hereditary Parkinson disease in the mid 1990's and studied its role in Parkinson disease for nearly 20 years. For his work on Parkinson disease, he was awarded the Klaus Joachim Zülch-Prize for Neurological Research and the Jay Van Andel Award for Outstanding Achievement in Parkinson's Disease Research. He also carried out positional cloning and characterization of the gene mutated in Lowe syndrome that led to accurate biochemical and molecular genetic testing, for which he has been recognized three times with awards from the Lowe Syndrome Association. He is the co-author of over 200 peer-reviewed publications on a broad range of topics in basic and applied human genetics and is co-author with Drs. Roderick M. McInnes and Huntington F. Willard of the popular textbook of human genetics, Thompson and Thompson's Genetics in Medicine. He has received numerous teaching awards from the University of Pennsylvania, the National Human Genome Research Institute and the University of California, San Francisco, and was awarded the Excellence in Education Award of the American Society of Human Genetics with his co-authors Drs. Willard and McInnes. Dr. Nussbaum is a Director and Treasurer of the American Board of Medical Genetics and Genomics and has served on the Board of Directors of the American College of Medical Genetics and Genomics and on the Board of the American Society of Human Genetics, where he also served as President. He was elected to the Institute of Medicine in 2004 and the American Academy of Arts and Sciences in 2015.


    As next generation sequencing has lowered the price of DNA sequencing orders of magnitude below what it cost to create the first consensus human genome, the sheer diversity of human sequence between individuals has become more and more apparent. This diversity is not only seen in single nucleotide variants but also deletions/duplications, insertions/deletions, and copy number variants.  Sorting the wheat from the chaff when performing molecular diagnostics of single-gene (Mendelian) disorders such as Hereditary Breast and Ovarian Cancer, Hypertrophic Cardiomyopathy, Hereditary Spastic Paraplegia, Cystic Fibrosis, is an enormous challenge because very serious medical decision making rests on a correct interpretation of the clinical meaning of variants, both in affected individuals and when sequencing is used for screening purposes.  The American College of Medical Genetics and the Association of Molecukar Pathologists took a first major step when they proposed that variant interpretations fall into one of five classes:  Benign, Likely Benign, Likely Pathogenic, Pathogenic, and Variant of Uncertain Significance (VUS). The also proposed a set of criteria to apply to guide the placement of any variant into on of these buckets. This proposal has improved the rigor and reproducibility of variant interpretation but much remains to be done to make variant interpretation more accurate and scalable if we are to deploy genomics more widely in medicine.

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