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

Journal Article (Journal 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.

Full Text

Duke Authors

Cited Authors

  • Zastrow, DB; Kohler, JN; Bonner, D; Reuter, CM; Fernandez, L; Grove, ME; Fisk, DG; Undiagnosed Diseases Network, ; Yang, Y; Eng, CM; Ward, PA; Bick, D; Worthey, EA; Fisher, PG; Ashley, EA; Bernstein, JA; Wheeler, MT

Published Date

  • April 2019

Published In

Volume / Issue

  • 28 / 2

Start / End Page

  • 213 - 228

PubMed ID

  • 30964584

Pubmed Central ID

  • PMC7385984

Electronic International Standard Serial Number (EISSN)

  • 1573-3599

Digital Object Identifier (DOI)

  • 10.1002/jgc4.1119


  • eng

Conference Location

  • United States