title: Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions.
abstract: OBJECTIVE
  Diagnostic exome sequencing was immediately successful in diagnosing patients in whom traditional technologies were uninformative. Herein, we provide the results from the first 500 probands referred to a clinical laboratory for diagnostic exome sequencing.
  
  
  METHODS
  Family-based exome sequencing included whole-exome sequencing followed by family inheritance-based model filtering, comprehensive medical review, familial cosegregation analysis, and analysis of novel genes.
  
  
  RESULTS
  A positive or likely positive result in a characterized gene was identified in 30% of patients (152/500). A novel gene finding was identified in 7.5% of patients (31/416). The highest diagnostic rates were observed among patients with ataxia, multiple congenital anomalies, and epilepsy (44, 36, and 35%, respectively). Twenty-three percent of positive findings were within genes characterized within the past 2 years. The diagnostic rate was significantly higher among families undergoing a trio (37%) as compared with a singleton (21%) whole-exome testing strategy.
  
  
  CONCLUSIONS
  Overall, we present results from the largest clinical cohort of diagnostic exome sequencing cases to date. These data demonstrate the utility of family-based exome sequencing and analysis to obtain the highest reported detection rate in an unselected clinical cohort, illustrating the utility of diagnostic exome sequencing as a transformative technology for the molecular diagnosis of genetic disease.
authors.affiliation: Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Kelly D
authors.initials: KD
authors.lastname: Farwell
authors.affiliation: Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Layla
authors.initials: L
authors.lastname: Shahmirzadi
authors.affiliation: Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Dima
authors.initials: D
authors.lastname: El-Khechen
authors.affiliation: Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Zöe
authors.initials: Z
authors.lastname: Powis
authors.affiliation: 1] Ambry Genetics, Aliso Viejo, California, USA [2] Division of Genetics and Metabolism, Department of Pediatrics, University of California, Irvine, Irvine, California, USA.
authors.forename: Elizabeth C
authors.identifier: 000000027684183X
authors.initials: EC
authors.lastname: Chao
authors.affiliation: Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Brigette
authors.initials: B
authors.lastname: Tippin Davis
authors.affiliation: Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Baxter
authors.affiliation: Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Zeng
authors.affiliation: Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Cameron
authors.initials: C
authors.lastname: Mroske
authors.affiliation: Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Parra
authors.affiliation: Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Gandomi
authors.affiliation: Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Ira
authors.initials: I
authors.lastname: Lu
authors.affiliation: Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.affiliation: Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Hsiao-Mei
authors.initials: HM
authors.lastname: Lu
authors.affiliation: Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Salvador
authors.affiliation: Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Ruble
authors.affiliation: Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Lao
authors.affiliation: Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Soren
authors.initials: S
authors.lastname: Fischbach
authors.affiliation: Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wen
authors.affiliation: Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Shela
authors.initials: S
authors.lastname: Lee
authors.affiliation: Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Elliott
authors.affiliation: Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Charles L M
authors.initials: CL
authors.lastname: Dunlop
authors.affiliation: Ambry Genetics, Aliso Viejo, California, USA.
authors.forename: Sha
authors.initials: S
authors.lastname: Tang
mesh_terms: D000328:Adult; D015331:Cohort Studies; D030541:Databases, Genetic; D059472:Exome; D005260:Female; D040941:Heredity; D006801:Humans; D008297:Male; D025202:Molecular Diagnostic Techniques / Q000379:methods / Q000706:statistics & numerical data*; D017422:Sequence Analysis, DNA / Q000379:methods / Q000706:statistics & numerical data*