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. 2019 Apr;28(2):213-228.
doi: 10.1002/jgc4.1119.

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

Diane B Zastrow  1 , Jennefer N Kohler  1 , Devon Bonner  1 , Chloe M Reuter  1 , Liliana Fernandez  1 , Megan E Grove  2 , Dianna G Fisk  2 ; Undiagnosed Diseases Network; Yaping Yang  3 , Christine M Eng  3 , Patricia A Ward  3 , David Bick  4 , Elizabeth A Worthey  4 , Paul G Fisher  1   5   6 , Euan A Ashley  1   2   7   8 , Jonathan A Bernstein  1   6 , Matthew T Wheeler  1   8
Collaborators, Affiliations

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

Diane B Zastrow et al. J Genet Couns. 2019 Apr.

Erratum in

  • Corrigendum.
    [No authors listed] [No authors listed] J Genet Couns. 2019 Aug;28(4):915. doi: 10.1002/jgc4.1136. Epub 2019 May 21. J Genet Couns. 2019. PMID: 31120166 No abstract available.

Abstract

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.

Keywords: exome sequencing; genome sequencing; rare diseases; sequencing reanalysis; undiagnosed diseases.

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Conflict of interest statement

Conflict of interest Diane B. Zastrow, Devon Bonner, Chloe Reuter, Jennefer N. Kohler, Liliana Fernandez, Megan E. Grove, Dianna G. Fisk, Yaping Yang, Christine M. Eng, Patricia A. Ward, David Bick, and Elizabeth A. Worthey declare that they have no conflict of interest. Euan A. Ashley is a founder and member of the scientific advisory board of Personalis and Deepcell. Euan A. Ashley is an advisor to Genome Medical and Sequencebio. Matthew T. Wheeler has a minor ownership interest in Personalis.

Figures

Figure 1.
Figure 1.. Lines of evidence used in evaluation of genomic findings.
Example characteristics contributing to variant-level, gene-level, and segregation evidence are listed. Each line of evidence (circle) is evaluated independently. Strong evidence in all three lines is indicative of a genomic diagnosis (center, light bulb). Strong evidence in two of three lines of evidence is of sufficient significance to pursue follow-up studies contributing to the third line of evidence (A star per line of evidence indicates strong evidence; question mark indicates a weak line of evidence).
Figure 2.
Figure 2.. Suggested workflow for non-diagnostic exome sequencing follow-up.
Based on type of results from exome sequencing, further steps for additional interrogation are displayed. These queries include additional testing, requesting additional data from sequencing laboratory, case matching, and phenotypic updates. VUS=variant(s) of unknown significance; Dx=diagnosis; N=no; Y=yes.
See this image and copyright information in PMC

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