A Randomized, Controlled Trial of the Analytic and Diagnostic Performance of Singleton and Trio, Rapid Genome and Exome Sequencing in Ill Infants.
diagnosis
genetic disease
genomic medicine
infant
intensive care unit
precision medicine
ultra-rapid whole-genome sequencing
whole-exome sequencing
whole-genome sequencing
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
03 10 2019
03 10 2019
Historique:
received:
03
07
2019
accepted:
23
08
2019
pubmed:
1
10
2019
medline:
3
4
2020
entrez:
1
10
2019
Statut:
ppublish
Résumé
The second Newborn Sequencing in Genomic Medicine and Public Health study was a randomized, controlled trial of the effectiveness of rapid whole-genome or -exome sequencing (rWGS or rWES, respectively) in seriously ill infants with diseases of unknown etiology. Here we report comparisons of analytic and diagnostic performance. Of 1,248 ill inpatient infants, 578 (46%) had diseases of unknown etiology. 213 infants (37% of those eligible) were enrolled within 96 h of admission. 24 infants (11%) were very ill and received ultra-rapid whole-genome sequencing (urWGS). The remaining infants were randomized, 95 to rWES and 94 to rWGS. The analytic performance of rWGS was superior to rWES, including variants likely to affect protein function, and ClinVar pathogenic/likely pathogenic variants (p < 0.0001). The diagnostic performance of rWGS and rWES were similar (18 diagnoses in 94 infants [19%] versus 19 diagnoses in 95 infants [20%], respectively), as was time to result (median 11.0 versus 11.2 days, respectively). However, the proportion diagnosed by urWGS (11 of 24 [46%]) was higher than rWES/rWGS (p = 0.004) and time to result was less (median 4.6 days, p < 0.0001). The incremental diagnostic yield of reflexing to trio after negative proband analysis was 0.7% (1 of 147). In conclusion, rapid genomic sequencing can be performed as a first-tier diagnostic test in inpatient infants. urWGS had the shortest time to result, which was important in unstable infants, and those in whom a genetic diagnosis was likely to impact immediate management. Further comparison of urWGS and rWES is warranted because genomic technologies and knowledge of variant pathogenicity are evolving rapidly.
Identifiants
pubmed: 31564432
pii: S0002-9297(19)30313-1
doi: 10.1016/j.ajhg.2019.08.009
pmc: PMC6817534
pii:
doi:
Types de publication
Journal Article
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
719-733Subventions
Organisme : NICHD NIH HHS
ID : U19 HD077693
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002550
Pays : United States
Investigateurs
Zaira Bezares
(Z)
Cinnamon Bloss
(C)
Joshua J A Braun
(JJA)
Carlos Diaz
(C)
Dana Mashburn
(D)
Dorjee Tamang
(D)
Daniken Orendain
(D)
Jenni Friedman
(J)
Joe Gleeson
(J)
Jaime Barea
(J)
George Chiang
(G)
Casey Cohenmeyer
(C)
Nicole G Coufal
(NG)
Marva Evans
(M)
Jose Honold
(J)
Raymond L Hovey
(RL)
Amy Kimball
(A)
Brian Lane
(B)
Crystal Le
(C)
Jennie Le
(J)
Sandra Leibel
(S)
Laurel Moyer
(L)
Patrick Mulrooney
(P)
Daeheon Oh
(D)
Paulina Ordonez
(P)
Albert Oriol
(A)
Maria Ortiz-Arechiga
(M)
Laura Puckett
(L)
Mark Speziale
(M)
Denise Suttner
(D)
Lucitia Van Der Kraan
(L)
Gail Knight
(G)
Charles Sauer
(C)
Richard Song
(R)
Sarah White
(S)
Audra Wise
(A)
Catherine Yamada
(C)
Informations de copyright
Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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