An automated 13.5 hour system for scalable diagnosis and acute management guidance for genetic diseases
Mallory Owen, Sébastien Lefebvre, Christian Holm Hansen, Chris M. Kunard, David Dimmock, Laurie D. Smith, Gunter Scharer, Rebecca Mardach, Mary Willis, Annette Feigenbaum, Anna‐Kaisa Niemi, Yan Ding, Luca Van Der Kraan, Katarzyna A. Ellsworth, Lucia Guidugli, Bryan R. Lajoie, Timothy K. McPhail, Shyamal Mehtalia, Kevin Chau, Yong Hyun Kwon, Zhanyang Zhu, Serge Batalov, Shimul Chowdhury, Seema Rego, James C. Perry, Mark Speziale, Mark Nespeca, Meredith S. Wright, Martin G. Reese, Francisco M. De La Vega, Joe Azure, Erwin Frise, Charlene Son Rigby, Sandy White, Charlotte A. Hobbs, Sheldon Gilmer, G. R. Knight, Albert Oriol, Jerica Lenberg, Shareef Nahas, Kate Perofsky, Kyu Kim, Jeanne Carroll, Nicole G. Coufal, Erica Sanford Kobayashi, Kristen Wigby, Jacqueline Weir, Vicki S. Thomson, Louise Fraser, Seka Lazare, Yoon H. Shin, Haiying Grunenwald, Richard Lee, David Jones, Duke Tran, Andrew M. Gross, Patrick Daigle, Anne Case, Marisa Lue, James A. Richardson, John Reynders, Thomas Defay, Kevin P. Hall, Narayanan Veeraraghavan, Stephen F. Kingsmore
Abstract
While many genetic diseases have effective treatments, they frequently progress rapidly to severe morbidity or mortality if those treatments are not implemented immediately. Since front-line physicians frequently lack familiarity with these diseases, timely molecular diagnosis may not improve outcomes. Herein we describe Genome-to-Treatment, an automated, virtual system for genetic disease diagnosis and acute management guidance. Diagnosis is achieved in 13.5 h by expedited whole genome sequencing, with superior analytic performance for structural and copy number variants. An expert panel adjudicated the indications, contraindications, efficacy, and evidence-of-efficacy of 9911 drug, device, dietary, and surgical interventions for 563 severe, childhood, genetic diseases. The 421 (75%) diseases and 1527 (15%) effective interventions retained are integrated with 13 genetic disease information resources and appended to diagnostic reports ( https://gtrx.radygenomiclab.com ). This system provided correct diagnoses in four retrospectively and two prospectively tested infants. The Genome-to-Treatment system facilitates optimal outcomes in children with rapidly progressive genetic diseases.