title: Molecular findings among patients referred for clinical whole-exome sequencing.
abstract: OBJECTIVE
  Clinical whole-exome sequencing is increasingly used for diagnostic evaluation of patients with suspected genetic disorders.
  
  
  OBJECTIVE
  To perform clinical whole-exome sequencing and report (1) the rate of molecular diagnosis among phenotypic groups, (2) the spectrum of genetic alterations contributing to disease, and (3) the prevalence of medically actionable incidental findings such as FBN1 mutations causing Marfan syndrome.
  
  
  METHODS
  Observational study of 2000 consecutive patients with clinical whole-exome sequencing analyzed between June 2012 and August 2014. Whole-exome sequencing tests were performed at a clinical genetics laboratory in the United States. Results were reported by clinical molecular geneticists certified by the American Board of Medical Genetics and Genomics. Tests were ordered by the patient's physician. The patients were primarily pediatric (1756 [88%]; mean age, 6 years; 888 females [44%], 1101 males [55%], and 11 fetuses [1% gender unknown]), demonstrating diverse clinical manifestations most often including nervous system dysfunction such as developmental delay.
  
  
  METHODS
  Whole-exome sequencing diagnosis rate overall and by phenotypic category, mode of inheritance, spectrum of genetic events, and reporting of incidental findings.
  
  
  RESULTS
  A molecular diagnosis was reported for 504 patients (25.2%) with 58% of the diagnostic mutations not previously reported. Molecular diagnosis rates for each phenotypic category were 143/526 (27.2%; 95% CI, 23.5%-31.2%) for the neurological group, 282/1147 (24.6%; 95% CI, 22.1%-27.2%) for the neurological plus other organ systems group, 30/83 (36.1%; 95% CI, 26.1%-47.5%) for the specific neurological group, and 49/244 (20.1%; 95% CI, 15.6%-25.8%) for the nonneurological group. The Mendelian disease patterns of the 527 molecular diagnoses included 280 (53.1%) autosomal dominant, 181 (34.3%) autosomal recessive (including 5 with uniparental disomy), 65 (12.3%) X-linked, and 1 (0.2%) mitochondrial. Of 504 patients with a molecular diagnosis, 23 (4.6%) had blended phenotypes resulting from 2 single gene defects. About 30% of the positive cases harbored mutations in disease genes reported since 2011. There were 95 medically actionable incidental findings in genes unrelated to the phenotype but with immediate implications for management in 92 patients (4.6%), including 59 patients (3%) with mutations in genes recommended for reporting by the American College of Medical Genetics and Genomics.
  
  
  CONCLUSIONS
  Whole-exome sequencing provided a potential molecular diagnosis for 25% of a large cohort of patients referred for evaluation of suspected genetic conditions, including detection of rare genetic events and new mutations contributing to disease. The yield of whole-exome sequencing may offer advantages over traditional molecular diagnostic approaches in certain patients.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Fan
authors.initials: F
authors.lastname: Xia
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Zhiyv
authors.initials: Z
authors.lastname: Niu
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Richard
authors.initials: R
authors.lastname: Person
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Patricia
authors.initials: P
authors.lastname: Ward
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Alicia
authors.initials: A
authors.lastname: Braxton
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Christian
authors.initials: C
authors.lastname: Buhay
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Narayanan
authors.initials: N
authors.lastname: Veeraraghavan
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Alicia
authors.initials: A
authors.lastname: Hawes
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Theodore
authors.initials: T
authors.lastname: Chiang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Magalie
authors.initials: M
authors.lastname: Leduc
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Joke
authors.initials: J
authors.lastname: Beuten
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Weimin
authors.initials: W
authors.lastname: He
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Scull
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Alecia
authors.initials: A
authors.lastname: Willis
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Megan
authors.initials: M
authors.lastname: Landsverk
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas3Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: William J
authors.initials: WJ
authors.lastname: Craigen
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Mir Reza
authors.initials: MR
authors.lastname: Bekheirnia
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: Asbjorg
authors.initials: A
authors.lastname: Stray-Pedersen
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Shu
authors.initials: S
authors.lastname: Wen
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Wendy
authors.initials: W
authors.lastname: Alcaraz
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Hong
authors.initials: H
authors.lastname: Cui
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Walkiewicz
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Reid
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bainbridge
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Ankita
authors.initials: A
authors.lastname: Patel
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas4Human Genetics Center, University of Texas Health Science Center, Houston.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Beaudet
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas2Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas3Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas3Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Plon
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas2Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Eng
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D059472:Exome; D005260:Female; D005333:Fetus; D030342:Genetic Diseases, Inborn / Q000175:diagnosis*; D005820:Genetic Testing; D023281:Genomics; D006801:Humans; D033162:Incidental Findings; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D025202:Molecular Diagnostic Techniques; D009154:Mutation; D010641:Phenotype; D012017:Referral and Consultation; D017422:Sequence Analysis, DNA / Q000379:methods*