Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort

Eur J Hum Genet. 2021 Jan;29(1):141-153. doi: 10.1038/s41431-020-00713-9. Epub 2020 Aug 28.


Despite clear technical superiority of genome sequencing (GS) over other diagnostic methods such as exome sequencing (ES), few studies are available regarding the advantages of its clinical application. We analyzed 1007 consecutive index cases for whom GS was performed in a diagnostic setting over a 2-year period. We reported pathogenic and likely pathogenic (P/LP) variants that explain the patients' phenotype in 212 of the 1007 cases (21.1%). In 245 additional cases (24.3%), a variant of unknown significance (VUS) related to the phenotype was reported. We especially investigated patients which had had ES with no genetic diagnosis (n = 358). For this group, GS diagnostic yield was 14.5% (52 patients with P/LP out of 358). GS should be especially indicated for ES-negative cases since up to 29.6% of them could benefit from GS testing (14.5% with P/LP, n = 52 and 15.1% with VUS, n = 54). Genetic diagnoses in most of the ES-negative/GS-positive cases were determined by technical superiority of GS, i.e., access to noncoding regions and more uniform coverage. Importantly, we reported 79 noncoding variants, of which, 41 variants were classified as P/LP. Interpretation of noncoding variants remains challenging, and in many cases, complementary methods based on direct enzyme assessment, biomarker testing and RNA analysis are needed for variant classification and diagnosis. We present the largest cohort of patients with GS performed in a clinical setting to date. The results of this study should direct the decision for GS as standard second-line, or even first-line stand-alone test.

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • Female
  • Gene Frequency
  • Genetic Diseases, Inborn / diagnosis*
  • Genetic Diseases, Inborn / epidemiology
  • Genetic Diseases, Inborn / genetics
  • Genetic Testing / standards*
  • Genetic Testing / statistics & numerical data
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Prenatal Diagnosis / standards
  • Prenatal Diagnosis / statistics & numerical data
  • Sensitivity and Specificity
  • Whole Exome Sequencing / standards*
  • Whole Exome Sequencing / statistics & numerical data