title: Diagnostic exome sequencing in persons with severe intellectual disability.
abstract: BACKGROUND
  The causes of intellectual disability remain largely unknown because of extensive clinical and genetic heterogeneity.
  
  
  METHODS
  We evaluated patients with intellectual disability to exclude known causes of the disorder. We then sequenced the coding regions of more than 21,000 genes obtained from 100 patients with an IQ below 50 and their unaffected parents. A data-analysis procedure was developed to identify and classify de novo, autosomal recessive, and X-linked mutations. In addition, we used high-throughput resequencing to confirm new candidate genes in 765 persons with intellectual disability (a confirmation series). All mutations were evaluated by molecular geneticists and clinicians in the context of the patients' clinical presentation.
  
  
  RESULTS
  We identified 79 de novo mutations in 53 of 100 patients. A total of 10 de novo mutations and 3 X-linked (maternally inherited) mutations that had been previously predicted to compromise the function of known intellectual-disability genes were found in 13 patients. Potentially causative de novo mutations in novel candidate genes were detected in 22 patients. Additional de novo mutations in 3 of these candidate genes were identified in patients with similar phenotypes in the confirmation series, providing support for mutations in these genes as the cause of intellectual disability. We detected no causative autosomal recessive inherited mutations in the discovery series. Thus, the total diagnostic yield was 16%, mostly involving de novo mutations.
  
  
  CONCLUSIONS
  De novo mutations represent an important cause of intellectual disability; exome sequencing was used as an effective diagnostic strategy for their detection. (Funded by the European Union and others.).
authors.affiliation: Department of Human Genetics, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Joep
authors.initials: J
authors.lastname: de Ligt
authors.forename: Marjolein H
authors.initials: MH
authors.lastname: Willemsen
authors.forename: Bregje W M
authors.initials: BW
authors.lastname: van Bon
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
authors.forename: Helger G
authors.initials: HG
authors.lastname: Yntema
authors.forename: Thessa
authors.initials: T
authors.lastname: Kroes
authors.forename: Anneke T
authors.initials: AT
authors.lastname: Vulto-van Silfhout
authors.forename: David A
authors.initials: DA
authors.lastname: Koolen
authors.forename: Petra
authors.initials: P
authors.lastname: de Vries
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.forename: Marisol
authors.initials: M
authors.lastname: del Rosario
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.forename: Hans
authors.initials: H
authors.lastname: Scheffer
authors.forename: Bert B A
authors.initials: BB
authors.lastname: de Vries
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
mesh_terms: D000293:Adolescent; D002648:Child; D059472:Exome / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive / Q000235:genetics; D050172:Genes, X-Linked; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D009154:Mutation; D017422:Sequence Analysis, DNA; D055815:Young Adult