A toolkit for genetics providers in follow-up of patients with non-diagnostic exome sequencing

Academic Article


  • There are approximately 7,000 rare diseases affecting 25–30 million Americans, with 80% estimated to have a genetic basis. This presents a challenge for genetics practitioners to determine appropriate testing, make accurate diagnoses, and conduct up-to-date patient management. Exome sequencing (ES) is a comprehensive diagnostic approach, but only 25%–41% of the patients receive a molecular diagnosis. The remaining three-fifths to three-quarters of patients undergoing ES remain undiagnosed. The Stanford Center for Undiagnosed Diseases (CUD), a clinical site of the Undiagnosed Diseases Network, evaluates patients with undiagnosed and rare diseases using a combination of methods including ES. Frequently these patients have non-diagnostic ES results, but strategic follow-up techniques identify diagnoses in a subset. We present techniques used at the CUD that can be adopted by genetics providers in clinical follow-up of cases where ES is non-diagnostic. Solved case examples illustrate different types of non-diagnostic results and the additional techniques that led to a diagnosis. Frequent approaches include segregation analysis, data reanalysis, genome sequencing, additional variant identification, careful phenotype-disease correlation, confirmatory testing, and case matching. We also discuss prioritization of cases for additional analyses.
  • Published In

    Digital Object Identifier (doi)

    Author List

  • Zastrow DB; Kohler JN; Bonner D; Reuter CM; Fernandez L; Grove ME; Fisk DG; Yang Y; Eng CM; Ward PA
  • Start Page

  • 213
  • End Page

  • 228
  • Volume

  • 28
  • Issue

  • 2