Utility of whole-genome sequencing for detection of newborn screening disorders in a population cohort of 1,696 neonates.
OBJECTIVE
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%).


CONCLUSIONS
WGS may help rule in and rule out NBS disorders, pinpoint molecular diagnoses, and detect conditions not amenable to current NBS assays.
Inova Translational Medicine Institute, Inova Health System, Falls Church, Virginia, USA.
Dale L
DL
Bodian
Inova Translational Medicine Institute, Inova Health System, Falls Church, Virginia, USA.
Elisabeth
E
Klein
Inova Translational Medicine Institute, Inova Health System, Falls Church, Virginia, USA.|Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
Ramaswamy K
RK
Iyer
Inova Translational Medicine Institute, Inova Health System, Falls Church, Virginia, USA.
Wendy S W
http://orcid.org/0000-0001-9850-3797
WS
Wong
Inova Translational Medicine Institute, Inova Health System, Falls Church, Virginia, USA.
Prachi
P
Kothiyal
Inova Translational Medicine Institute, Inova Health System, Falls Church, Virginia, USA.
Daniel
D
Stauffer
Inova Translational Medicine Institute, Inova Health System, Falls Church, Virginia, USA.
Kathi C
KC
Huddleston
Department of Pediatrics, Inova Children's Hospital, Inova Health System, Falls Church, Virginia, USA.
Amber D
AD
Gaither
Department of Pediatrics, Inova Children's Hospital, Inova Health System, Falls Church, Virginia, USA.
Irina
I
Remsburg
Inova Translational Medicine Institute, Inova Health System, Falls Church, Virginia, USA.
Alina
A
Khromykh
Fairfax Neonatal Associates, Inova Health System, Falls Church, Virginia, USA.
Robin L
RL
Baker
Department of Obstetrics and Gynecology, Inova Fairfax Hospital, Falls Church, Virginia, USA.|Women's Health Integrated Research Center at Inova Health System, Falls Church, Virginia, USA.|Department of Defense Gynecologic Cancer Center of Excellence, Annandale, Virginia, USA.
George L
GL
Maxwell
Inova Translational Medicine Institute, Inova Health System, Falls Church, Virginia, USA.|Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
Joseph G
http://orcid.org/0000-0002-9749-3934
JG
Vockley
Inova Translational Medicine Institute, Inova Health System, Falls Church, Virginia, USA.|Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
John E
JE
Niederhuber
Inova Translational Medicine Institute, Inova Health System, Falls Church, Virginia, USA.|Department of Pediatrics, Inova Children's Hospital, Inova Health System, Falls Church, Virginia, USA.|Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
Benjamin D
BD
Solomon
D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D015997:Neonatal Screening / Q000379:methods*; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA / Q000379:methods*