Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Jan;21(1):161-172.
doi: 10.1038/s41436-018-0044-2. Epub 2018 Jun 15.

A comprehensive iterative approach is highly effective in diagnosing individuals who are exome negative

Vandana Shashi  1 , Kelly Schoch  2 , Rebecca Spillmann  2 , Heidi Cope  2 , Queenie K-G Tan  2 , Nicole Walley  2 , Loren Pena  2 , Allyn McConkie-Rosell  2 , Yong-Hui Jiang  2 , Nicholas Stong  3 , Anna C Need  4 , David B Goldstein  3 ; Undiagnosed Diseases Network
Collaborators, Affiliations

A comprehensive iterative approach is highly effective in diagnosing individuals who are exome negative

Vandana Shashi et al. Genet Med. 2019 Jan.

Abstract

Purpose: Sixty to seventy-five percent of individuals with rare and undiagnosed phenotypes remain undiagnosed after exome sequencing (ES). With standard ES reanalysis resolving 10-15% of the ES negatives, further approaches are necessary to maximize diagnoses in these individuals.

Methods: In 38 ES negative patients an individualized genomic-phenotypic approach was employed utilizing (1) phenotyping; (2) reanalyses of FASTQ files, with innovative bioinformatics; (3) targeted molecular testing; (4) genome sequencing (GS); and (5) conferring of clinical diagnoses when pathognomonic clinical findings occurred.

Results: Certain and highly likely diagnoses were made in 18/38 (47%) individuals, including identifying two new developmental disorders. The majority of diagnoses (>70%) were due to our bioinformatics, phenotyping, and targeted testing identifying variants that were undetected or not prioritized on prior ES. GS diagnosed 3/18 individuals with structural variants not amenable to ES. Additionally, tentative diagnoses were made in 3 (8%), and in 5 individuals (13%) candidate genes were identified. Overall, diagnoses/potential leads were identified in 26/38 (68%).

Conclusions: Our comprehensive approach to ES negatives maximizes the ES and clinical data for both diagnoses and candidate gene identification, without GS in the majority. This iterative approach is cost-effective and is pertinent to the current conundrum of ES negatives.

Keywords: Exome sequencing; Genome sequencing; Phenotyping; Rare diseases; Undiagnosed diseases.

PubMed Disclaimer

Conflict of interest statement

Conflicts of Interest

David Goldstein is a founder of and holds equity in Pairnomix and Praxis, serves as a consultant to AstraZeneca, and has research supported by Janssen, Gilead, Biogen, AstraZeneca, and UCB.

The rest of the authors declare no conflicts of interest related to this manuscript.

Figures

Figure 1
Figure 1
Flowchart illustrating the approach to the ES negatives and the resolution with the different modalities
See this image and copyright information in PMC

References

    1. Lee H, Deignan JL, Dorrani N, et al. Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA. 2014;312(18):1880–1887. - PMC - PubMed
    1. Gilissen C, Hoischen A, Brunner HG, Veltman JA. Unlocking Mendelian disease using exome sequencing. Genome Biol. 2011;12(9):228. - PMC - PubMed
    1. Need AC, Shashi V, Hitomi Y, et al. Clinical application of exome sequencing in undiagnosed genetic conditions. J Med Genet. 2012;49(6):353–361. - PMC - PubMed
    1. Yang Y, Muzny DM, Xia F, et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA. 2014;312(18):1870–1879. - PMC - PubMed
    1. Wenger AM, Guturu H, Bernstein JA, Bejerano G. Systematic reanalysis of clinical exome data yields additional diagnoses: implications for providers. Genet Med. 2017;19(2):209–214. - PubMed

Publication types