A semiautomated whole-exome sequencing workflow leads to increased diagnostic yield and identification of novel candidate variants

Cold Spring Harb Mol Case Stud. 2019 Apr 1;5(2):a003756. doi: 10.1101/mcs.a003756. Print 2019 Apr.


Advancing the clinical utility of whole-exome sequencing (WES) for patients with suspected genetic disorders is largely driven by bioinformatics approaches that streamline data processing and analysis. Herein, we describe our experience with implementing a semiautomated and phenotype-driven WES diagnostic workflow, incorporating both the DRAGEN pipeline and the Exomiser variant prioritization tool, at an academic children's hospital with an ethnically diverse pediatric patient population. We achieved a 41% molecular diagnostic rate for 66 duo-, quad-, or trio-WES cases, and 28% for 40 singleton-WES cases. Preliminary results were returned to ordering physicians within 1 wk for 12 of 38 (32%) probands with positive findings, which were instrumental in guiding the appropriate clinical management for a variety of patients, especially in critical care settings. The semiautomated and streamlined WES workflow also enabled us to identify novel variants in candidate disease genes in patients with developmental delay and autism and immune disorders and cancer, including ANK2, BPTF, BCL11A, FOXN1, PLAA, ATRX, DNAJC21, and RAD50 Together, we demonstrated the implementation of a streamlined WES workflow that was successfully applied for both clinical and research purposes.

Keywords: abnormality of the cerebral vasculature; acute myeloid leukemia; aggressive behavior; ambiguous genitalia, male; aplasia of the thymus; astrocytoma; ataxia; autism; bilateral cryptorchidism; cleft palate; delayed social development; generalized hypotonia due to defect at the neuromuscular junction; generalized tonic seizures; microcephaly; osteosarcoma; retinoblastoma; severe T-cell immunodeficiency; severe global developmental delay; short stature; webbed neck.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Autism Spectrum Disorder / diagnosis*
  • Autism Spectrum Disorder / genetics
  • Child
  • Child, Preschool
  • Early Diagnosis
  • Exome Sequencing / methods*
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Immune System Diseases / diagnosis*
  • Immune System Diseases / genetics
  • Infant
  • Infant, Newborn
  • Male
  • Neoplasms / diagnosis*
  • Neoplasms / genetics
  • Sensitivity and Specificity
  • Time Factors
  • Workflow
  • Young Adult