title: Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders.
abstract: Neurodevelopmental disorders (NDDs) affect more than 3% of children and are attributable to single-gene mutations at more than 1000 loci. Traditional methods yield molecular diagnoses in less than one-half of children with NDD. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) can enable diagnosis of NDD, but their clinical and cost-effectiveness are unknown. One hundred families with 119 children affected by NDD received diagnostic WGS and/or WES of parent-child trios, wherein the sequencing approach was guided by acuity of illness. Forty-five percent received molecular diagnoses. An accelerated sequencing modality, rapid WGS, yielded diagnoses in 73% of families with acutely ill children (11 of 15). Forty percent of families with children with nonacute NDD, followed in ambulatory care clinics (34 of 85), received diagnoses: 33 by WES and 1 by staged WES then WGS. The cost of prior negative tests in the nonacute patients was $19,100 per family, suggesting sequencing to be cost-effective at up to $7640 per family. A change in clinical care or impression of the pathophysiology was reported in 49% of newly diagnosed families. If WES or WGS had been performed at symptom onset, genomic diagnoses may have been made 77 months earlier than occurred in this study. It is suggested that initial diagnostic evaluation of children with NDD should include trio WGS or WES, with extension of accelerated sequencing modalities to high-acuity patients.
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy-Kansas City, Kansas City, MO 64108, USA. Department of Pediatrics, Children's Mercy-Kansas City, Kansas City, MO 64108, USA. School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA. ssoden@cmh.edu.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Soden
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy-Kansas City, Kansas City, MO 64108, USA. Department of Pediatrics, Children's Mercy-Kansas City, Kansas City, MO 64108, USA. School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA. Department of Pathology, Children's Mercy-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-Kansas City, Kansas City, MO 64108, USA. Department of Pediatrics, Children's Mercy-Kansas City, 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-Kansas City, Kansas City, MO 64108, USA. Department of Pediatrics, Children's Mercy-Kansas City, Kansas City, MO 64108, USA. School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA. Department of Pathology, Children's Mercy-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-Kansas City, Kansas City, MO 64108, USA. Department of Pediatrics, Children's Mercy-Kansas City, 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: Center for Pediatric Genomic Medicine, Children's Mercy-Kansas City, Kansas City, MO 64108, USA. Department of Pediatrics, Children's Mercy-Kansas City, 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-Kansas City, Kansas City, MO 64108, USA. Department of Pediatrics, Children's Mercy-Kansas City, Kansas City, MO 64108, USA. School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: LePichon
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy-Kansas City, Kansas City, MO 64108, USA. Department of Pediatrics, Children's Mercy-Kansas City, 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-Kansas City, Kansas City, MO 64108, USA. School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA. Department of Pathology, Children's Mercy-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Thiffault
authors.affiliation: Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA. Clinical and Translational Science Center, University of New Mexico Health Sciences 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-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Greyson
authors.initials: G
authors.lastname: Twist
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Noll
authors.affiliation: Department of Pediatrics, Children's Mercy-Kansas City, Kansas City, MO 64108, USA. School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Bryce A
authors.initials: BA
authors.lastname: Heese
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy-Kansas City, Kansas City, MO 64108, USA. Department of Pathology, Children's Mercy-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Zellmer
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy-Kansas City, Kansas City, MO 64108, USA. Department of Pediatrics, Children's Mercy-Kansas City, Kansas City, MO 64108, USA. School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Atherton
authors.affiliation: Department of Pediatrics, Children's Mercy-Kansas City, Kansas City, MO 64108, USA. School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Ahmed T
authors.initials: AT
authors.lastname: Abdelmoity
authors.affiliation: Department of Pediatrics, Children's Mercy-Kansas City, Kansas City, MO 64108, USA. School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Safina
authors.affiliation: Department of Pediatrics, Children's Mercy-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Nyp
authors.affiliation: Department of Pediatrics, Children's Mercy-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Britton
authors.initials: B
authors.lastname: Zuccarelli
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy-Kansas City, Kansas City, MO 64108, USA. Department of Pediatrics, Children's Mercy-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Larson
authors.affiliation: Department of Pediatrics, Children's Mercy-Kansas City, Kansas City, MO 64108, USA. School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Modrcin
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy-Kansas City, Kansas City, MO 64108, USA. Department of Pediatrics, Children's Mercy-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Herd
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Creed
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Xuan
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Brodsky
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy-Kansas City, Kansas City, MO 64108, USA. Department of Pediatrics, Children's Mercy-Kansas City, Kansas City, MO 64108, USA. School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA. Department of Pathology, Children's Mercy-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Kingsmore
mesh_terms: D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000175:diagnosis* / Q000235:genetics*; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D016678:Genome; D015894:Genome, Human; D017048:Health Care Costs; D006801:Humans; D007223:Infant; D008297:Male; D025202:Molecular Diagnostic Techniques / Q000379:methods; D009154:Mutation; D010641:Phenotype; D017422:Sequence Analysis, DNA / Q000379:methods