Abstract
BackgroundExome sequencing has advanced to clinical practice and proven useful for obtaining molecular diagnoses in rare diseases. In approximately 75 % of cases, however, a clinical exome study does not produce a definitive molecular diagnosis. These residual cases comprise a new diagnostic challenge for the genetics community. The Undiagnosed Diseases Program of the National Institutes of Health routinely utilizes exome sequencing for refractory clinical cases. Our preliminary data suggest that disease-causing variants may be missed by current standard-of-care clinical exome analysis. Such false negatives reflect limitations in experimental design, technical performance, and data analysis.ResultsWe present examples from our datasets to quantify the analytical performance associated with current practices, and explore strategies to improve the completeness of data analysis. In particular, we focus on patient ascertainment, exome capture, inclusion of intronic variants, and evaluation of medium-sized structural variants.ConclusionsThe strategies we present may recover previously-missed, disease causing variants in second-pass exome analysis. Understanding the limitations of the current clinical exome search space provides a rational basis to improve methods for disease variant detection using genome-scale sequencing techniques.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-016-0216-3) contains supplementary material, which is available to authorized users.
Highlights
Exome sequencing has advanced to clinical practice and proven useful for obtaining molecular diagnoses in rare diseases
The Undiagnosed Diseases Program (UDP) of the National Institutes of Health (NIH) was established in 2008 to evaluate patients who were undiagnosed despite an extensive medical workup [1,2,3]
Patients A growing number of pediatric patients referred to the UDP present with prior unrevealing clinical exome studies (Fig. 1a), which necessitates the development of novel diagnostic strategies to improve experimental power
Summary
Exome sequencing has advanced to clinical practice and proven useful for obtaining molecular diagnoses in rare diseases. In approximately 75 % of cases, a clinical exome study does not produce a definitive molecular diagnosis. These residual cases comprise a new diagnostic challenge for the genetics community. The Undiagnosed Diseases Program of the National Institutes of Health routinely utilizes exome sequencing for refractory clinical cases. Our preliminary data suggest that disease-causing variants may be missed by current standard-of-care clinical exome analysis. Such false negatives reflect limitations in experimental design, technical performance, and data analysis. We employed an extended set of analytic approaches to identify disease-causing variants beyond those detected by current clinical exome analysis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
