title: A 26-hour system of highly sensitive whole genome sequencing for emergency management of genetic diseases.
abstract: While the cost of whole genome sequencing (WGS) is approaching the realm of routine medical tests, it remains too tardy to help guide the management of many acute medical conditions. Rapid WGS is imperative in light of growing evidence of its utility in acute care, such as in diagnosis of genetic diseases in very ill infants, and genotype-guided choice of chemotherapy at cancer relapse. In such situations, delayed, empiric, or phenotype-based clinical decisions may meet with substantial morbidity or mortality. We previously described a rapid WGS method, STATseq, with a sensitivity of >96 % for nucleotide variants that allowed a provisional diagnosis of a genetic disease in 50 h. Here improvements in sequencing run time, read alignment, and variant calling are described that enable 26-h time to provisional molecular diagnosis with >99.5 % sensitivity and specificity of genotypes. STATseq appears to be an appropriate strategy for acutely ill patients with potentially actionable genetic diseases.
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy, 2401 Gilham Road, Kansas City, MO, 64108, USA.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Miller
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy, 2401 Gilham Road, Kansas City, MO, 64108, USA.|Department of Pediatrics, Children's Mercy, Kansas City, MO, 64108, USA.|Department of Pathology, Children's Mercy, Kansas City, MO, 64108, USA.|School of Medicine, University of Missouri-Kansas City, Kansas City, MO, 64108, USA.
authors.forename: Emily G
authors.initials: EG
authors.lastname: Farrow
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy, 2401 Gilham Road, Kansas City, MO, 64108, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Gibson
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy, 2401 Gilham Road, Kansas City, MO, 64108, USA.|Department of Pediatrics, Children's Mercy, Kansas City, MO, 64108, USA.|School of Medicine, University of Missouri-Kansas City, Kansas City, MO, 64108, USA.
authors.forename: Laurel K
authors.initials: LK
authors.lastname: Willig
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy, 2401 Gilham Road, Kansas City, MO, 64108, USA.
authors.forename: Greyson
authors.initials: G
authors.lastname: Twist
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy, 2401 Gilham Road, Kansas City, MO, 64108, USA.
authors.forename: Byunggil
authors.initials: B
authors.lastname: Yoo
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy, 2401 Gilham Road, Kansas City, MO, 64108, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Marrs
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy, 2401 Gilham Road, Kansas City, MO, 64108, USA.
authors.forename: Shane
authors.initials: S
authors.lastname: Corder
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy, 2401 Gilham Road, Kansas City, MO, 64108, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Krivohlavek
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy, 2401 Gilham Road, Kansas City, MO, 64108, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Walter
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy, 2401 Gilham Road, Kansas City, MO, 64108, USA.|Department of Pediatrics, Children's Mercy, Kansas City, MO, 64108, USA.|School of Medicine, University of Missouri-Kansas City, Kansas City, MO, 64108, USA.
authors.forename: Josh E
authors.initials: JE
authors.lastname: Petrikin
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy, 2401 Gilham Road, Kansas City, MO, 64108, USA.|Department of Pediatrics, Children's Mercy, Kansas City, MO, 64108, USA.|Department of Pathology, Children's Mercy, Kansas City, MO, 64108, USA.|School of Medicine, University of Missouri-Kansas City, Kansas City, MO, 64108, USA.
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Saunders
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy, 2401 Gilham Road, Kansas City, MO, 64108, USA.|Department of Pathology, Children's Mercy, Kansas City, MO, 64108, USA.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Thiffault
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy, 2401 Gilham Road, Kansas City, MO, 64108, USA.|Department of Pediatrics, Children's Mercy, Kansas City, MO, 64108, USA.|School of Medicine, University of Missouri-Kansas City, Kansas City, MO, 64108, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Soden
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy, 2401 Gilham Road, Kansas City, MO, 64108, USA.|Department of Pediatrics, Children's Mercy, Kansas City, MO, 64108, USA.|Department of Pathology, Children's Mercy, Kansas City, MO, 64108, USA.|School of Medicine, University of Missouri-Kansas City, Kansas City, MO, 64108, USA.
authors.forename: Laurie D
authors.initials: LD
authors.lastname: Smith
authors.affiliation: Deparment of Pediatrics, and Clinical Translational Science Center, University of New Mexico Health Science Center, Albuquerque, NM, 87131, USA.
authors.forename: Darrell L
authors.initials: DL
authors.lastname: Dinwiddie
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy, 2401 Gilham Road, Kansas City, MO, 64108, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Herd
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy, 2401 Gilham Road, Kansas City, MO, 64108, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Cakici
authors.affiliation: Edico Genome, Inc., 3344 North Torrey Pines Court, Plaza Level, La Jolla, CA, 92037, USA.
authors.forename: Severine
authors.initials: S
authors.lastname: Catreux
authors.affiliation: Edico Genome, Inc., 3344 North Torrey Pines Court, Plaza Level, La Jolla, CA, 92037, USA.
authors.forename: Mike
authors.initials: M
authors.lastname: Ruehle
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy, 2401 Gilham Road, Kansas City, MO, 64108, USA. skingsmore@rchsd.org.|Department of Pediatrics, Children's Mercy, Kansas City, MO, 64108, USA. skingsmore@rchsd.org.|Department of Pathology, Children's Mercy, Kansas City, MO, 64108, USA. skingsmore@rchsd.org.|School of Medicine, University of Missouri-Kansas City, Kansas City, MO, 64108, USA. skingsmore@rchsd.org.|Rady Pediatric Genomics and Systems Medicine Institute, Rady Chlildren's Hospital, 3020 Children's Way, San Diego, CA, 92123, USA. skingsmore@rchsd.org.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Kingsmore
mesh_terms: D003955:Diagnostic Tests, Routine; D030342:Genetic Diseases, Inborn / Q000175:diagnosis / Q000235:genetics*; D015894:Genome, Human; D006801:Humans; D017422:Sequence Analysis, DNA / Q000379:methods*