A Randomized, Controlled Trial of the Analytic and Diagnostic Performance of Singleton and Trio, Rapid Genome and Exome Sequencing in Ill Infants.

Autor:	Kingsmore SF; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA. Electronic address: skingsmore@rchsd.org., Cakici JA; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Department of Family Medicine and Public Health, University of California San Diego, San Diego, CA 92093, USA., Clark MM; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA., Gaughran M; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA., Feddock M; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA., Batalov S; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA., Bainbridge MN; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA., Carroll J; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Department of Pediatrics, University of California San Diego, San Diego, CA 92093, USA., Caylor SA; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA., Clarke C; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA., Ding Y; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA., Ellsworth K; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA., Farnaes L; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Department of Pediatrics, University of California San Diego, San Diego, CA 92093, USA., Hildreth A; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Department of Pediatrics, University of California San Diego, San Diego, CA 92093, USA; Department of Pediatrics, University of Washington, Seattle, WA 98195, USA., Hobbs C; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA., James K; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA., Kint CI; Diploid, 3001 Leuven, Belgium., Lenberg J; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA., Nahas S; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA., Prince L; Department of Pediatrics, University of California San Diego, San Diego, CA 92093, USA., Reyes I; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA., Salz L; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA., Sanford E; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Department of Pediatrics, University of California San Diego, San Diego, CA 92093, USA., Schols P; Diploid, 3001 Leuven, Belgium., Sweeney N; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Department of Pediatrics, University of California San Diego, San Diego, CA 92093, USA., Tokita M; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA., Veeraraghavan N; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA., Watkins K; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA., Wigby K; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Department of Pediatrics, University of California San Diego, San Diego, CA 92093, USA., Wong T; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA., Chowdhury S; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA., Wright MS; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA., Dimmock D; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2019 Oct 03; Vol. 105 (4), pp. 719-733. Date of Electronic Publication: 2019 Sep 26.
DOI:	10.1016/j.ajhg.2019.08.009
Abstrakt:	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. (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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