title: Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios.
abstract: OBJECTIVE
  Despite the recognized clinical value of exome-based diagnostics, methods for comprehensive genomic interpretation remain immature. Diagnoses are based on known or presumed pathogenic variants in genes already associated with a similar phenotype. Here, we extend this paradigm by evaluating novel bioinformatics approaches to aid identification of new gene-disease associations.
  
  
  METHODS
  We analyzed 119 trios to identify both diagnostic genotypes in known genes and candidate genotypes in novel genes. We considered qualifying genotypes based on their population frequency and in silico predicted effects we also characterized the patterns of genotypes enriched among this collection of patients.
  
  
  RESULTS
  We obtained a genetic diagnosis for 29 (24%) of our patients. We showed that patients carried an excess of damaging de novo mutations in intolerant genes, particularly those shown to be essential in mice (P = 3.4 × 10(-8)). This enrichment is only partially explained by mutations found in known disease-causing genes.
  
  
  CONCLUSIONS
  This work indicates that the application of appropriate bioinformatics analyses to clinical sequence data can also help implicate novel disease genes and suggest expanded phenotypes for known disease genes. These analyses further suggest that some cases resolved by whole-exome sequencing will have direct therapeutic implications.
authors.affiliation: Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA.|Department of Medicine, University of Melbourne, Austin Health and Royal Melbourne Hospital, Melbourne, Australia.
authors.forename: Slavé
authors.initials: S
authors.lastname: Petrovski
authors.affiliation: Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA.|Present address: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Pingxing
authors.initials: P
authors.lastname: Xie
authors.affiliation: Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Ruzzo
authors.affiliation: Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Lu
authors.affiliation: Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: K Melodi
authors.initials: KM
authors.lastname: McSweeney
authors.affiliation: Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.|Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Bruria
authors.initials: B
authors.lastname: Ben-Zeev
authors.affiliation: Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.|Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Andreea
authors.initials: A
authors.lastname: Nissenkorn
authors.affiliation: Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.|Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Yair
authors.initials: Y
authors.lastname: Anikster
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Danit
authors.initials: D
authors.lastname: Oz-Levi
authors.affiliation: Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Ryan S
authors.identifier: http://orcid.org/0000-0002-8965-0813
authors.initials: RS
authors.lastname: Dhindsa
authors.affiliation: Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA.|Present address: Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hitomi
authors.affiliation: Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Schoch
authors.affiliation: Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Spillmann
authors.affiliation: Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.|Pinchas Borenstein Talpiot Medical Leadership Program, Pediatric Neurology Unit, Chaim Sheba Medical Center, Tel HaShomer, Israel.
authors.forename: Gali
authors.initials: G
authors.lastname: Heimer
authors.affiliation: Metabolic Disease Unit, Edmond and Lily Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Dina
authors.initials: D
authors.lastname: Marek-Yagel
authors.affiliation: Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.|Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Tzadok
authors.affiliation: Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Gordon
authors.initials: G
authors.lastname: Worley
authors.affiliation: Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Goldstein
authors.affiliation: Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA.|Department of Neurobiology, Duke University, Durham, North Carolina, USA.
authors.forename: Yong-Hui
authors.initials: YH
authors.lastname: Jiang
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Doron
authors.initials: D
authors.lastname: Lancet
authors.affiliation: Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel.|Danek Gertner Institute of Human Genetics, Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Elon
authors.initials: E
authors.lastname: Pras
authors.affiliation: Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Vandana
authors.initials: V
authors.lastname: Shashi
authors.affiliation: UCB NewMedicines, Slough, UK.
authors.forename: Duncan
authors.identifier: http://orcid.org/0000-0002-3763-4643
authors.initials: D
authors.lastname: McHale
authors.affiliation: Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA.|Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Need
authors.affiliation: Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
mesh_terms: D019295:Computational Biology / Q000379:methods; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D030342:Genetic Diseases, Inborn / Q000175:diagnosis* / Q000235:genetics*; D023281:Genomics / Q000379:methods; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype