Practical considerations in the clinical application of whole‐exome sequencing

Abstract

Despite the exciting advent of whole-exome sequencing (WES) in medical genetics practices, the optimal interpretation of results requires further actions such as reconsidering clinical information and obtaining further laboratory testing. There are no published data to guide clinicians in this process. In a retrospective study on 93 patients who underwent clinical WES, we set out to assess and resolve these practical challenges. With the laboratories reporting a molecular diagnostic rate of 25.8%, the medical geneticists and the laboratories were 90% concordant in their interpretation of the WES results. Divergence occurred when the medical geneticist reconsidered clinical information and/or additional information regarding pathogenicity of a variant. Variants of uncertain significance were reported in 86% of patients, with 53.7% needing follow-up, such as additional laboratory tests and genotyping of family members. By layering clinical data (e.g. mode of inheritance and phenotypic fit) on to the laboratory results, we developed clinical categories for the WES results. These categories of definite diagnosis (14/93), likely diagnosis (8/93), possible diagnosis (13/93) and no diagnosis (58/93) could be used to convey results to patients uniformly. Our framework for a clinically informed interpretation of the results enhances the utility of WES within medical genetics practices.

Clinical exome sequencing: results from 2819 samples reflecting 1000 families

“…37 The overall strategy of our clinical WES workflow is a very intensive collaboration with clinicians before, during, and after WES analysis to provide relevant molecular findings. The essential benefit of close cooperation not only lies in the identification of formerly unknown diseases caused by rare genetic variants, as shown in a separate case reports of our results on novel asparagine synthetase deficiency and skeletal ciliopathy, 38, 39 but also allowing future evidence based evaluation by providing combined genetic and clinical information.…”

Defining the Clinical Value of a Genomic Diagnosis in the Era of Next-Generation Sequencing

“…Furthermore, after variant results are returned and subjected to clinical correlation by clinicians who are involved in the patient's care, opportunities for communicating additional information to the laboratory for iterative interpretation of the variant data are limited. In fact, comparison of the overall interpretation of 93 clinical exome sequencing results between clinicians and laboratories demonstrated that when discrepancies occurred (which they did in approximately 10% of cases), they often involved additional clinical information that was subsequently considered in the interpretation of the result (113). As genome-scale sequencing becomes more common in medical care, it is imperative that clinicians and laboratories develop standards for communication about phenotypes and genotypes (both the presence and absence of specific findings) and that formal channels are made available for back-and-forth discussions.…”

Family-Specific Variants and the Limits of Human Genetics

“…We believe that a clear understanding of both population genetics and medical diagnostics principles can lead to variant interpretation that may mitigate the proliferation of VUS while facilitating open communication. Bending the linear relationship between DNA sequenced and VUS reported to patients by appropriately classifying a higher proportion of rare variants and reducing the number of VUS reported per gene, might help address concerns about VUS (Blazer et al, 2015, Culver et al, 2013, Murray et al, 2011, Richter et al, 2013, Shashi et al, 2016) and aid in fostering societal acceptance of clinical exome and genome scale sequencing. If this does not happen, then patients reading genomic sequencing reports risk missing critical information because of long lists of VUS (Blazer et al, 2015, Culver et al, 2013, Murray et al, 2011, Richter et al, 2013, Shashi et al, 2016).…”