Proband-Only Clinical Exome Sequencing for Neurodevelopmental Disabilities

Pediatr Neurol. 2019 Oct;99:47-54. doi: 10.1016/j.pediatrneurol.2019.02.017. Epub 2019 Feb 27.


Background: Whole exome sequencing on family trios gives the highest diagnostic yield, but high cost limits its application. Here, we performed proband-only clinical exome sequencing in a population of patients with neurodevelopmental disabilities and tested the diagnostic yield.

Methods: This observational, retrospective study included 108 unrelated patients with neurodevelopmental disabilities who underwent clinical exome sequencing at the outpatient clinics of the Severance Children's Hospital, Seoul, South Korea, between March 2017 and May 2018. Clinical exome sequencing targeted 4503 disease-causing genes.

Results: The overall diagnostic rate was 38.0% (41 of 108) when proband-only clinical exome sequencing was performed without additional parental testing. Four sequence variants were reclassified as likely pathogenic after parental testing, representing an additional 3.7% of the diagnostic yield. The final diagnostic rate was 41.7% (45 of 108). Of 45 patients with genetic abnormalities, a total of 38 sequence variations were detected in 33 (30.6%) patients with five homozygous cases, and 13 chromosomal copy number variants were detected in 12 (11.1%) patients. Novel variants of known causal genes for neurodevelopmental disabilities were detected in 18 (16.7%) patients. These were variants that could be reclassified as likely pathogenic if the de novo nature of the mutation was confirmed after testing of parental samples.

Conclusions: Proband-only clinical exome sequencing is a practical diagnostic tool that may be implemented in the clinical setting for patients with neurodevelopmental disabilities. A cost-effective approach to neurodevelopmental disabilities would be a proband-only clinical exome sequencing followed by parental testing of selective candidate variants.

Keywords: Children; Intellectual disability; Neurodiagnostics.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / epidemiology
  • Abnormalities, Multiple / genetics
  • Age of Onset
  • Causality
  • Child
  • Child, Preschool
  • Chromosome Aberrations
  • Comorbidity
  • Consensus
  • DNA Copy Number Variations
  • Exome Sequencing* / economics
  • Female
  • Genetic Association Studies
  • Genotype
  • High-Throughput Nucleotide Sequencing*
  • Humans
  • Infant
  • Infant, Premature
  • Intellectual Disability / epidemiology
  • Intellectual Disability / genetics
  • Male
  • Molecular Sequence Annotation
  • Mutation
  • Neurodevelopmental Disorders / diagnosis
  • Neurodevelopmental Disorders / epidemiology
  • Neurodevelopmental Disorders / genetics*
  • Parents
  • Pedigree
  • Republic of Korea / epidemiology
  • Retrospective Studies
  • Seizures / epidemiology
  • Seizures / genetics