Clinical exome sequencing: results from 2819 samples reflecting 1000 families

Eur J Hum Genet. 2017 Feb;25(2):176-182. doi: 10.1038/ejhg.2016.146. Epub 2016 Nov 16.


We report our results of 1000 diagnostic WES cases based on 2819 sequenced samples from 54 countries with a wide phenotypic spectrum. Clinical information given by the requesting physicians was translated to HPO terms. WES processes were performed according to standardized settings. We identified the underlying pathogenic or likely pathogenic variants in 307 families (30.7%). In further 253 families (25.3%) a variant of unknown significance, possibly explaining the clinical symptoms of the index patient was identified. WES enabled timely diagnosing of genetic diseases, validation of causality of specific genetic disorders of PTPN23, KCTD3, SCN3A, PPOX, FRMPD4, and SCN1B, and setting dual diagnoses by detecting two causative variants in distinct genes in the same patient. We observed a better diagnostic yield in consanguineous families, in severe and in syndromic phenotypes. Our results suggest that WES has a better yield in patients that present with several symptoms, rather than an isolated abnormality. We also validate the clinical benefit of WES as an effective diagnostic tool, particularly in nonspecific or heterogeneous phenotypes. We recommend WES as a first-line diagnostic in all cases without a clear differential diagnosis, to facilitate personal medical care.

Publication types

  • Evaluation Study

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Exome*
  • Female
  • Flavoproteins / genetics
  • Genetic Testing / methods*
  • Genetic Testing / standards
  • Genotyping Techniques / methods*
  • Genotyping Techniques / standards
  • Humans
  • Infant
  • Infant, Newborn
  • Intracellular Signaling Peptides and Proteins / genetics
  • Male
  • Middle Aged
  • Mitochondrial Proteins / genetics
  • NAV1.3 Voltage-Gated Sodium Channel / genetics
  • Nuclear Family
  • Phenotype
  • Potassium Channels / genetics
  • Protein Tyrosine Phosphatases, Non-Receptor / genetics
  • Protoporphyrinogen Oxidase / genetics
  • Sequence Analysis, DNA / methods*
  • Sequence Analysis, DNA / standards
  • Sodium Channels / genetics
  • Voltage-Gated Sodium Channel beta-1 Subunit / genetics


  • FRMPD4 protein, human
  • Flavoproteins
  • Intracellular Signaling Peptides and Proteins
  • KCTD3 protein, human
  • Mitochondrial Proteins
  • NAV1.3 Voltage-Gated Sodium Channel
  • Potassium Channels
  • SCN1B protein, human
  • SCN3A protein, human
  • Sodium Channels
  • Voltage-Gated Sodium Channel beta-1 Subunit
  • PPOX protein, human
  • Protoporphyrinogen Oxidase
  • PTPN23 protein, human
  • Protein Tyrosine Phosphatases, Non-Receptor