An Evidence-Based Dosage Sensitivity Map Towards Defining the Clinical Genome. E. Riggs1, E. Andersen2, B. Hong2, H. Kearney3, G. Hislop4, S. Kantarci5, D. Pineda-Alvarez6, U. Maye7, D. McMullan8, M. Serrano2, I. Simonic9, S. South2, M. Speevak10, K. Smith11, J. Stavropoulos12, K. Wain3, S. Aradhya13, E. Thorland3, C. Martin1 on behalf of the Clinical Genome (ClinGen) Resource 1) Autism and Developmental Medicine Institute, Geisinger Health System, Lewisburg, PA; 2) Dept of Pediatrics and Pathology, ARUP Laboratories, Univ of Utah, Salt Lake City, UT; 3) Dept of Lab Medicine & Pathology, Mayo Clinic, Rochester, MN; 4) Ninewells Hospital, Dundee, United Kingdom; 5) Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA; 6) GeneDx, Gaithersburg, MD; 7) Liverpool Womens Hospital, Liverpool, United Kingdom; 8) West Midlands Regional Genetics Laboratories, Birmingham, United Kingdom; 9) Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom; 10) CVH Site, Trillium Health Partners; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; 11) Sheffield Childrens Hospital, Sheffield, United Kingdom; 12) Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada; 13) InVitae, San Francisco, CA.

   The Clinical Genome (ClinGen) Resource is an NIH-funded program dedicated to developing community resources for sharing, analyzing, and curating human genomic variant data to advance genomic medicine. Continuing work initiated as part of the International Standards for Cytogenomic Arrays (ISCA) Consortium and the International Collaboration for Clinical Genomics (ICCG), the ClinGen Structural Variation Working Group is creating a dynamic, genome-wide dosage sensitivity map towards defining the clinical genome. We are using an evidence-based process to evaluate whether haploinsufficiency (loss) or triplosensitivity (gain) of particular genes and genomic regions result in clinically demonstrable phenotypes. We defined five categories for level of evidence including: sufficient evidence, emerging evidence, little evidence, no evidence and dosage sensitivity unlikely. We have currently evaluated a total of 541 genes/genomic regions. Of these, a total of 257 met our criteria for sufficient evidence supporting a role for dosage sensitivity in human disease (47%). These genes/genomic regions are now included in our curated catalog of known pathogenic copy number losses and gains, which is continually updated as new genes/regions are reviewed and is publically available at www.ncbi.nlm.nih.gov/projects/dbvar/ISCA/ or through dbVar (study nstd45). This valuable resource can be used as a guide for clinical interpretation of copy number variants (CNV) throughout the genome. For example, CNVs encompassing one or more genes with sufficient evidence for dosage sensitivity should be interpreted as pathogenic, whereas those containing genes with only limited or no evidence might be interpreted as uncertain. The use of this resource extends beyond the individual laboratory setting, and will be used as part of the ClinGen project to mitigate inter-laboratory conflicts in CNV data submitted from clinical and research laboratories to the ClinVar and dbGaP databases at NCBI. These CNVs will be compared against our evolving dosage sensitivity map and evaluated by expert review. This process will allow us to resolve some of the current discrepancies in available data, providing additional curated resources for interpretation of CNVs throughout the genome. The ongoing evaluation of dosage sensitivity using an evidence-based process will lead to standardized clinical interpretations and play a critical role in incorporating genomic medicine into patient care.

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