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. 2016 Jul;18(7):678-85.
doi: 10.1038/gim.2015.142. Epub 2015 Dec 3.

Molecular diagnostic experience of whole-exome sequencing in adult patients

Jennifer E Posey  1 , Jill A Rosenfeld  1 , Regis A James  2 , Matthew Bainbridge  1   3 , Zhiyv Niu  1   4 , Xia Wang  1 , Shweta Dhar  1   5 , Wojciech Wiszniewski  1 , Zeynep H C Akdemir  1 , Tomasz Gambin  1 , Fan Xia  1   4 , Richard E Person  1   4 , Magdalena Walkiewicz  1   4 , Chad A Shaw  1 , V Reid Sutton  1 , Arthur L Beaudet  1 , Donna Muzny  1   3 , Christine M Eng  1   4 , Yaping Yang  1   4 , Richard A Gibbs  1   3   4 , James R Lupski  1   3   6   7 , Eric Boerwinkle  3   8 , Sharon E Plon  1   3   6   7   9
Affiliations

Molecular diagnostic experience of whole-exome sequencing in adult patients

Jennifer E Posey et al. Genet Med. 2016 Jul.

Abstract

Purpose: Whole-exome sequencing (WES) is increasingly used as a diagnostic tool in medicine, but prior reports focus on predominantly pediatric cohorts with neurologic or developmental disorders. We describe the diagnostic yield and characteristics of WES in adults.

Methods: We performed a retrospective analysis of consecutive WES reports for adults from a diagnostic laboratory. Phenotype composition was determined using Human Phenotype Ontology terms.

Results: Molecular diagnoses were reported for 17.5% (85/486) of adults, which is lower than that for a primarily pediatric population (25.2%; P = 0.0003); the diagnostic rate was higher (23.9%) for those 18-30 years of age compared to patients older than 30 years (10.4%; P = 0.0001). Dual Mendelian diagnoses contributed to 7% of diagnoses, revealing blended phenotypes. Diagnoses were more frequent among individuals with abnormalities of the nervous system, skeletal system, head/neck, and growth. Diagnostic rate was independent of family history information, and de novo mutations contributed to 61.4% of autosomal dominant diagnoses.

Conclusion: Early WES experience in adults demonstrates molecular diagnoses in a substantial proportion of patients, informing clinical management, recurrence risk, and recommendations for relatives. A positive family history was not predictive, consistent with molecular diagnoses often revealed by de novo events, informing the Mendelian basis of genetic disease in adults.Genet Med 18 7, 678-685.

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Conflict of interest statement

CONFLICT OF INTEREST

Baylor College of Medicine (BCM) and Miraca Holdings Inc. have formed a joint venture with shared ownership and governance of the Baylor Miraca Genetics Laboratories (BMGL), which performs clinical exome sequencing. JAR, ZN, FX, REP, MW, ALB, CME, YY, RAG, JRL, and SEP are employees of BCM and derive support through a professional services agreement with the BMGL. SEP and JRL serve on the Scientific Advisory Board of the BMGL. RAG serves as interim Chief Scientific Officer of the BMGL. ALB serves as Chief Medical Officer of the BMGL.

MB is the founder of Codified Genomics Inc., and derives personal fees from Illumina Inc. SD is the CEO and co-founder of PanGenomics Clinical Genetics Center in India. JAR reports personal fees from Signature Genomic Laboratories, PerkinElmer, Inc., in the past 36 months. RAG reports consulting fees from GE-Clarient. JRL has stock ownership in 23 and Me, is a paid consultant for Regeneron Pharmaceuticals, has stock options in Lasergen, Inc and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases and bacterial genomic fingerprinting. Other authors have no disclosures relevant to the manuscript.

Other authors have no potential conflicts to disclose.

Figures

Figure 1
Figure 1. Age and sex of individuals undergoing WES
(A) Total number of female (dark grey) and male (light grey) cases by age group. * indicates p<0.05 for significance of differences between male and female proportions within each age group. (B) Molecular diagnostic rate as percentage of total cases in each age group.
Figure 2
Figure 2. Phenotypic spectrum of individuals undergoing WES
(A) Scaled representation of relative frequency of each phenotype class within this series. Individual cases may be counted in multiple classes. (B) Diagnostic rate for each phenotype class [grey bars, left y-axis] and percent of all cases for each phenotype class [blue line, right y-axis]. * indicates Monte Carlo p<0.05 for the association between diagnostic rate and phenotype class.
See this image and copyright information in PMC

Comment in

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