title: 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.
authors: Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC, USA.
authors: V
authors: V
authors: Shashi
authors: Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC, USA.
authors: A
authors: A
authors: McConkie-Rosell
authors: Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC, USA.
authors: K
authors: K
authors: Schoch
authors: Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC, USA.
authors: V
authors: V
authors: Kasturi
authors: Department of Pathology, Duke University Medical Center, Durham, NC, USA.
authors: C
authors: C
authors: Rehder
authors: Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC, USA.
authors: Y H
authors: YH
authors: Jiang
authors: Center for Human Genome Variation, Duke University Medical Center, Durham, NC, USA.
authors: D B
authors: DB
authors: Goldstein
authors: Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC, USA.
authors: M T
authors: MT
authors: McDonald
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003710:Demography; D059472:Exome / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D033162:Incidental Findings; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D017422:Sequence Analysis, DNA / Q000379:methods*; D055815:Young Adult
keywords: clinical genetics; medical genetics; next-generation sequencing; practice utilization; whole-exome sequencing