616 - Gene List Development for the BEACONS study: The First U.S. Multi-State Genomic Newborn Screening Initiative

Publication Number: 4603.616

Harini Somanchi, Massachusetts General Hospital, Herndon, VA, United States; Britt Johnson, GeneDx, LLC, Fort Lauderdale, FL, United States; Amber Begtrup, GeneDx, Cincinnati, OH, United States; Charles J. Billington, University of Minnesota Medical School, Minneapolis, MN, United States; Steven E.. Brenner, University of California, Berkeley, Berkeley, CA, United States; Manish J. Butte, University of California, Los Angeles David Geffen School of Medicine, Los Angeles, CA, United States; Scott Canna, Childrens Hospital of Philadelphia, Philadelphia, PA, United States; Samuel Chiang, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States; Stephanie Coury, Mass General Brigham, Subdury, MA, United States; Ottavia M. Delmonte, National Institutes of Health, NIAID, Bethesda, MD, United States; Lisa Diller, Dana-Farber Cancer Institute, Boston, MA, United States; Rebecca Ganetzky, Children's Hospital of Philadelphia, Philadelphia, PA, United States; Jessica Gold, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY, United States; Eyal Grunebaum, The Hospital for Sick Children, Toronto, ON, Canada; Rebecca Hale, Boston Children's Hospital, Brookline, MA, United States; Ada Hamosh, Johns Hopkins University, Baltimore, MD, United States; Alexander Holtz, Boston Children's Hospital, Boston, MA, United States; Matthew J. Kan, University of California, San Francisco, School of Medicine, San Francisco, CA, United States; Dalia Kasperaviciute, Genomics England, London, England, United Kingdom; Maleewan Kitcharoensakkul, Washington University in St. Louis School of Medicine, Saint Louis, MO, United States; Katherine G. Langley, GeneDx, Henrico, VA, United States; Joshua D.. Milner, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, United States; Thomas Minten, KU Leuven, Leuven, Vlaams-Brabant, Belgium; Deborah M. Mitchell, Massachusetts General Hospital, Boston, MA, United States; Xiao P. Peng, Albert Einstein College of Medicine, New York, NY, United States; Emily M. Place, Mass Eye and Ear, Boston, MA, United States; Craig D. Platt, Boston Children's Hospital, Boston, MA, United States; Sharon E. Plon, Baylor College of Medicine, Houston, TX, United States; Jennifer M. Puck, University of California, San Francisco, School of Medicine, San Francisco, CA, United States; Heidi L. Rehm, Massachusetts General Hospital, Boston, MA, United States; Amy Roberts, Boston Children's Hospital, Boston, MA, United States; Vijay G. Sankaran, Boston Children's Hospital/HHMI, Boston, MA, United States; Daniella M. Schwartz, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Christine Seroogy, University of Wisconsin, Madison, WI, United States; Alanna Strong, Childrens Hospital of Philadelphia, Philadelphia, PA, United States; Kathleen E. Sullivan, Childrens Hospital of Philadelphia, Philadelphia, PA, United States; Weizhen Tan, MGB for Children, Boston, MA, United States; Teresa K.. Tarrant, Duke University School of Medicine, Durham, NC, United States; Jay Thiagarajah, Boston Children's Hospital, Boston, MA, United States; Melissa A. Walker, Massachusetts General Hospital/ Harvard Medical School, Boston, MA, United States; Carrie Blout Zawatsky, Brigham and Women's Hospital, Ariadne Labs, Boston, MA, United States; Rebekah Zimmerman, GeneDx, Maplewood, NJ, United States; Hannie Zomer-Bolanos, UT Southwestern, Dallas, TX, United States; Robert Green, Harvard Medical School, Boston, MA, United States; Ingrid A. Holm, Harvard Medical School, Boston, MA, United States; Melissa Wasserstein, Children's Hospital at Montefiore/Albert Einstein College of Medicine, Bronx, NY, United States; Nina Gold, MassGeneral Hospital for Children, Boston, MA, United States

Background: Whole genome sequencing (WGS) has the potential to expand newborn screening (NBS) by enabling the detection of additional treatable conditions that are not identifiable by standard biochemical methods. The Building Evidence and Collaboration for GenOmics in Nationwide Newborn Screening (BEACONS) study is the first research program to integrate WGS into multiple U.S. state public health laboratories and aims to sequence up to 30,000 newborns. A primary aim is to determine which genes and variants should be included, given variation in disease age of onset, severity, and clinical actionability. Prior studies have demonstrated that there is substantial heterogeneity in the gene lists used by many genomic NBS research programs.

Objective: To develop an evidence-based, expert-informed, community-endorsed gene list focused on conditions with onset and targeted surveillance or treatment in the first year of life, to be used in multi-state public health genomic newborn sequencing.

Design/Methods: We first compiled genes from four sources: (1) core and secondary conditions from the U.S. Recommended Uniform Screening Panel (RUSP), (2) disorders considered actionable in the first week of life, (3) disorders included in ≥2 prior genomic newborn screening studies or commercial panels and with ≥50% endorsement in a survey of rare disease specialists, (4) those included by at least two of the other major public health genomic NBS studies. These genes were then curated to determine whether they were actionable in the first year of life and if they aligned with recently published consensus criteria from the International Consortium of Newborn Sequencing (ICoNS) on gene list selection. The draft gene list was then circulated to clinical experts, state public health laboratories, the BEACONS Community Advisory Board, and the general public for iterative review and refinement.

Results: The initial gene list draft included 475 genes, associated with inherited metabolic disorders (n = 157, 33%), inborn errors of immunity (n = 100, 21%), and endocrine disorders (n = 73, 15%), among other clinical areas. Only 60 (13%) were associated with core RUSP conditions, and 415 (87%) were associated with other disorders.

The final version of the gene list, incorporating feedback from a wide range of key informants, will be completed by January 2026 and presented.

Conclusion(s): BEACONS has established a consensus-driven, evidence-based gene list that can be used in research across multiple state public health laboratories, enabling the prospective evaluation of feasibility of population-wide genomic NBS.