title: Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnosed diseases.
abstract: Diagnostic exome sequencing (DES) is now a commonly ordered test for individuals with undiagnosed genetic disorders. In addition to providing a diagnosis for characterized diseases, exome sequencing has the capacity to uncover novel candidate genes for disease.
  
  
  
  Family-based DES included analysis of both characterized and novel genetic etiologies. To evaluate candidate genes for disease in the clinical setting, we developed a systematic, rule-based classification schema.
  
  
  
  Testing identified a candidate gene among 7.7% (72/934) of patients referred for DES; 37 (4.0%) and 35 (3.7%) of the genes received evidence scores of "candidate" and "suspected candidate," respectively. A total of 71 independent candidate genes were reported among the 72 patients, and 38% (27/71) were subsequently corroborated in the peer-reviewed literature. This rate of corroboration increased to 51.9% (27/52) among patients whose gene was reported at least 12 months previously.
  
  
  
  Herein, we provide transparent, comprehensive, and standardized scoring criteria for the clinical reporting of candidate genes. These results demonstrate that DES is an integral tool for genetic diagnosis, especially for elucidating the molecular basis for both characterized and novel candidate genetic etiologies. Gene discoveries also advance the understanding of normal human biology and more common diseases.Genet Med 19 2, 224-235.
authors: Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
authors: Kelly D
authors: 0000-0003-1173-052X
authors: KD
authors: Farwell Hagman
authors: Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
authors: Deepali N
authors: 0000-0002-4782-6868
authors: DN
authors: Shinde
authors: Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
authors: Cameron
authors: 0000-0002-8182-9931
authors: C
authors: Mroske
authors: Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
authors: Erica
authors: 0000-0002-5424-580X
authors: E
authors: Smith
authors: Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
authors: Kelly
authors: 0000-0001-7310-0174
authors: K
authors: Radtke
authors: Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
authors: Layla
authors: 0000-0002-7684-183X
authors: L
authors: Shahmirzadi
authors: Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
authors: Dima
authors: 0000-0002-6540-7181
authors: D
authors: El-Khechen
authors: Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
authors: Zöe
authors: 0000-0002-1347-4358
authors: Z
authors: Powis
authors: Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.|Division of Genetics and Genomics, Department of Pediatrics, University of California, Irvine, Irvine, California, USA.
authors: Elizabeth C
authors: 0000-0002-4082-371X
authors: EC
authors: Chao
authors: Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
authors: Wendy A
authors: WA
authors: Alcaraz
authors: Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
authors: Katherine L
authors: 0000-0001-8249-0549
authors: KL
authors: Helbig
authors: Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
authors: Samin A
authors: SA
authors: Sajan
authors: Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
authors: Mari
authors: 0000-0001-9012-9219
authors: M
authors: Rossi
authors: Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
authors: Hsiao-Mei
authors: HM
authors: Lu
authors: Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
authors: Robert
authors: R
authors: Huether
authors: Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
authors: Shuwei
authors: 0000-0001-7176-1964
authors: S
authors: Li
authors: Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
authors: Sitao
authors: 0000-0002-4740-8885
authors: S
authors: Wu
authors: Department of Genetics, Kaiser Permanente, San Diego, California, USA.
authors: Mark E
authors: 0000-0001-6338-1726
authors: ME
authors: Nuñes
authors: Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
authors: Sha
authors: 0000-0002-8304-2286
authors: S
authors: Tang
mesh_terms: D030541:Databases, Genetic; D059472:Exome / Q000235:genetics; D056726:Genetic Association Studies; D030342:Genetic Diseases, Inborn / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D009154:Mutation; D000073359:Exome Sequencing