title: A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders.
abstract: To prospectively evaluate the diagnostic and clinical utility of singleton whole-exome sequencing (WES) as a first-tier test in infants with suspected monogenic disease.
  
  
  
  Singleton WES was performed as a first-tier sequencing test in infants recruited from a single pediatric tertiary center. This occurred in parallel with standard investigations, including single- or multigene panel sequencing when clinically indicated. The diagnosis rate, clinical utility, and impact on management of singleton WES were evaluated.
  
  
  
  Of 80 enrolled infants, 46 received a molecular genetic diagnosis through singleton WES (57.5%) compared with 11 (13.75%) who underwent standard investigations in the same patient group. Clinical management changed following exome diagnosis in 15 of 46 diagnosed participants (32.6%). Twelve relatives received a genetic diagnosis following cascade testing, and 28 couples were identified as being at high risk of recurrence in future pregnancies.
  
  
  
  This prospective study provides strong evidence for increased diagnostic and clinical utility of singleton WES as a first-tier sequencing test for infants with a suspected monogenic disorder. Singleton WES outperformed standard care in terms of diagnosis rate and the benefits of a diagnosis, namely, impact on management of the child and clarification of reproductive risks for the extended family in a timely manner.Genet Med 18 11, 1090-1096.
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia.
authors.forename: Zornitza
authors.identifier: 0000-0001-8640-1371
authors.initials: Z
authors.lastname: Stark
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia.|University of Melbourne, Melbourne, Australia.
authors.forename: Tiong Y
authors.initials: TY
authors.lastname: Tan
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia.
authors.forename: Belinda
authors.initials: B
authors.lastname: Chong
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia.|Melbourne Genomics Health Alliance, Melbourne, Australia.
authors.forename: Gemma R
authors.identifier: 0000-0003-0133-7994
authors.initials: GR
authors.lastname: Brett
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia.
authors.forename: Patrick
authors.identifier: 0000-0002-3175-1136
authors.initials: P
authors.lastname: Yap
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia.
authors.forename: Maie
authors.initials: M
authors.lastname: Walsh
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia.
authors.forename: Alison
authors.initials: A
authors.lastname: Yeung
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia.|University of Melbourne, Melbourne, Australia.|Royal Children's Hospital, Melbourne, Australia.
authors.forename: Heidi
authors.initials: H
authors.lastname: Peters
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia.|University of Melbourne, Melbourne, Australia.|Royal Children's Hospital, Melbourne, Australia.
authors.forename: Dylan
authors.identifier: 0000-0002-9775-0603
authors.initials: D
authors.lastname: Mordaunt
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia.
authors.forename: Shannon
authors.initials: S
authors.lastname: Cowie
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia.|University of Melbourne, Melbourne, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Amor
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia.|University of Melbourne, Melbourne, Australia.
authors.forename: Ravi
authors.initials: R
authors.lastname: Savarirayan
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia.
authors.forename: George
authors.initials: G
authors.lastname: McGillivray
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia.
authors.forename: Lilian
authors.initials: L
authors.lastname: Downie
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia.|University of Melbourne, Melbourne, Australia.
authors.forename: Paul G
authors.identifier: 0000-0002-2976-8617
authors.initials: PG
authors.lastname: Ekert
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia.|University of Melbourne, Melbourne, Australia.|Royal Women's Hospital, Melbourne, Australia.
authors.forename: Christiane
authors.identifier: 0000-0001-7577-6004
authors.initials: C
authors.lastname: Theda
authors.affiliation: Royal Melbourne Hospital, Melbourne, Australia.
authors.forename: Paul A
authors.initials: PA
authors.lastname: James
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia.|Royal Children's Hospital, Melbourne, Australia.
authors.forename: Joy
authors.identifier: 0000-0002-6158-6215
authors.initials: J
authors.lastname: Yaplito-Lee
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia.|University of Melbourne, Melbourne, Australia.|Royal Children's Hospital, Melbourne, Australia.
authors.forename: Monique M
authors.initials: MM
authors.lastname: Ryan
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia.|University of Melbourne, Melbourne, Australia.|Royal Children's Hospital, Melbourne, Australia.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Leventer
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia.|Melbourne Genomics Health Alliance, Melbourne, Australia.|Royal Melbourne Hospital, Melbourne, Australia.
authors.forename: Emma
authors.initials: E
authors.lastname: Creed
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia.
authors.forename: Ivan
authors.identifier: 0000-0002-0908-8542
authors.initials: I
authors.lastname: Macciocca
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia.
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Bell
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia.|University of Melbourne, Melbourne, Australia.
authors.forename: Alicia
authors.initials: A
authors.lastname: Oshlack
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia.
authors.forename: Simon
authors.initials: S
authors.lastname: Sadedin
authors.affiliation: University of Melbourne, Melbourne, Australia.
authors.forename: Peter
authors.identifier: 0000-0002-5096-4735
authors.initials: P
authors.lastname: Georgeson
authors.affiliation: University of Melbourne, Melbourne, Australia.
authors.forename: Charlotte
authors.identifier: 0000-0003-3310-3834
authors.initials: C
authors.lastname: Anderson
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia.|University of Melbourne, Melbourne, Australia.|Melbourne Genomics Health Alliance, Melbourne, Australia.
authors.forename: Natalie
authors.initials: N
authors.lastname: Thorne
authors.lastname: Melbourne Genomics Health Alliance
authors.affiliation: University of Melbourne, Melbourne, Australia.|Melbourne Genomics Health Alliance, Melbourne, Australia.
authors.forename: Clara
authors.initials: C
authors.lastname: Gaff
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Australia.|University of Melbourne, Melbourne, Australia.
authors.forename: Susan M
authors.identifier: 0000-0001-7611-634X
authors.initials: SM
authors.lastname: White
mesh_terms: D059472:Exome / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000175:diagnosis* / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D007231:Infant, Newborn; D057089:Pathology, Molecular