title: Clinical application of whole-exome sequencing across clinical indications.
abstract: We report the diagnostic yield of whole-exome sequencing (WES) in 3,040 consecutive cases at a single clinical laboratory.
  
  
  
  WES was performed for many different clinical indications and included the proband plus two or more family members in 76% of cases.
  
  
  
  The overall diagnostic yield of WES was 28.8%. The diagnostic yield was 23.6% in proband-only cases and 31.0% when three family members were analyzed. The highest yield was for patients who had disorders involving hearing (55%, N = 11), vision (47%, N = 60), the skeletal muscle system (40%, N = 43), the skeletal system (39%, N = 54), multiple congenital anomalies (36%, N = 729), skin (32%, N = 31), the central nervous system (31%, N = 1,082), and the cardiovascular system (28%, N = 54). Of 2,091 cases in which secondary findings were analyzed for 56 American College of Medical Genetics and Genomics-recommended genes, 6.2% (N = 129) had reportable pathogenic variants. In addition to cases with a definitive diagnosis, in 24.2% of cases a candidate gene was reported that may later be reclassified as being associated with a definitive diagnosis.
  
  
  
  Our experience with our first 3,040 WES cases suggests that analysis of trios significantly improves the diagnostic yield compared with proband-only testing for genetically heterogeneous disorders and facilitates identification of novel candidate genes.Genet Med 18 7, 696-704.
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Kyle
authors.identifier: 0000-0001-5252-2001
authors.initials: K
authors.lastname: Retterer
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Juusola
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Megan T
authors.identifier: 0000-0001-5666-5376
authors.initials: MT
authors.lastname: Cho
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Patrik
authors.initials: P
authors.lastname: Vitazka
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Francisca
authors.initials: F
authors.lastname: Millan
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Federica
authors.identifier: 0000-0002-5047-6520
authors.initials: F
authors.lastname: Gibellini
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Annette
authors.initials: A
authors.lastname: Vertino-Bell
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.|Takeda Pharmaceuticals International, Inc., Deerfield, Illinois, USA.
authors.forename: Nizar
authors.initials: N
authors.lastname: Smaoui
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.|Pathway Genomics Corporation, San Diego, California, USA.
authors.forename: Julie
authors.identifier: 0000-0003-0962-1957
authors.initials: J
authors.lastname: Neidich
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Kristin G
authors.identifier: 0000-0003-3406-1250
authors.initials: KG
authors.lastname: Monaghan
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Dianalee
authors.initials: D
authors.lastname: McKnight
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Renkui
authors.initials: R
authors.lastname: Bai
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Suchy
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Bethany
authors.initials: B
authors.lastname: Friedman
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.|Invitae, San Francisco, California, USA.
authors.forename: Jackie
authors.initials: J
authors.lastname: Tahiliani
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Daniel
authors.identifier: 0000-0002-0580-058X
authors.initials: D
authors.lastname: Pineda-Alvarez
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Richard
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Tracy
authors.initials: T
authors.lastname: Brandt
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.|Invitae, San Francisco, California, USA.
authors.forename: Eden
authors.identifier: 0000-0002-2126-0982
authors.initials: E
authors.lastname: Haverfield
authors.affiliation: Department of Pediatrics, Columbia University, New York, New York, USA.|Department of Medicine, Columbia University, New York, New York, USA.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.affiliation: GeneDx, Gaithersburg, Maryland, USA.
authors.forename: Sherri
authors.initials: S
authors.lastname: Bale
mesh_terms: D059472:Exome / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000145:classification / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D009154:Mutation; D017422:Sequence Analysis, DNA / Q000379:methods