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Sci Transl Med. 2014 Dec 3;6(265):265ra168. doi: 10.1126/scitranslmed.3010076.

Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders.

Author information

1
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.
2
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.
3
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.
4
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.
5
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.
6
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.
7
Center for Pediatric Genomic Medicine, Children's Mercy-Kansas City, Kansas City, MO 64108, USA.
8
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.
9
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.
10
Department of Pediatrics, Children's Mercy-Kansas City, Kansas City, MO 64108, USA.
11
Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.

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.

PMID:
25473036
PMCID:
PMC4286868
DOI:
10.1126/scitranslmed.3010076
[Indexed for MEDLINE]
Free PMC Article
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