Dale L Bodian1, Elisabeth Klein1, Ramaswamy K Iyer1,2, Wendy S W Wong1, Prachi Kothiyal1, Daniel Stauffer1, Kathi C Huddleston1, Amber D Gaither3, Irina Remsburg3, Alina Khromykh1, Robin L Baker4, George L Maxwell5,6,7, Joseph G Vockley1,2, John E Niederhuber1,8, Benjamin D Solomon1,3,9. 1. Inova Translational Medicine Institute, Inova Health System, Falls Church, Virginia, USA. 2. Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA. 3. Department of Pediatrics, Inova Children's Hospital, Inova Health System, Falls Church, Virginia, USA. 4. Fairfax Neonatal Associates, Inova Health System, Falls Church, Virginia, USA. 5. Department of Obstetrics and Gynecology, Inova Fairfax Hospital, Falls Church, Virginia, USA. 6. Women's Health Integrated Research Center at Inova Health System, Falls Church, Virginia, USA. 7. Department of Defense Gynecologic Cancer Center of Excellence, Annandale, Virginia, USA. 8. Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 9. Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
Abstract
PURPOSE: To assess the potential of whole-genome sequencing (WGS) to replicate and augment results from conventional blood-based newborn screening (NBS). METHODS: Research-generated WGS data from an ancestrally diverse cohort of 1,696 infants and both parents of each infant were analyzed for variants in 163 genes involved in disorders included or under discussion for inclusion in US NBS programs. WGS results were compared with results from state NBS and related follow-up testing. RESULTS: NBS genes are generally well covered by WGS. There is a median of one (range: 0-6) database-annotated pathogenic variant in the NBS genes per infant. Results of WGS and NBS in detecting 28 state-screened disorders and four hemoglobin traits were concordant for 88.6% of true positives (n = 35) and 98.9% of true negatives (n = 45,757). Of the five infants affected with a state-screened disorder, WGS identified two whereas NBS detected four. WGS yielded fewer false positives than NBS (0.037 vs. 0.17%) but more results of uncertain significance (0.90 vs. 0.013%). CONCLUSION: WGS may help rule in and rule out NBS disorders, pinpoint molecular diagnoses, and detect conditions not amenable to current NBS assays.
PURPOSE: To assess the potential of whole-genome sequencing (WGS) to replicate and augment results from conventional blood-based newborn screening (NBS). METHODS: Research-generated WGS data from an ancestrally diverse cohort of 1,696 infants and both parents of each infant were analyzed for variants in 163 genes involved in disorders included or under discussion for inclusion in US NBS programs. WGS results were compared with results from state NBS and related follow-up testing. RESULTS: NBS genes are generally well covered by WGS. There is a median of one (range: 0-6) database-annotated pathogenic variant in the NBS genes per infant. Results of WGS and NBS in detecting 28 state-screened disorders and four hemoglobin traits were concordant for 88.6% of true positives (n = 35) and 98.9% of true negatives (n = 45,757). Of the five infants affected with a state-screened disorder, WGS identified two whereas NBS detected four. WGS yielded fewer false positives than NBS (0.037 vs. 0.17%) but more results of uncertain significance (0.90 vs. 0.013%). CONCLUSION: WGS may help rule in and rule out NBS disorders, pinpoint molecular diagnoses, and detect conditions not amenable to current NBS assays.
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