title: Whole-exome sequencing is a powerful approach for establishing the etiological diagnosis in patients with intellectual disability and microcephaly.
abstract: BACKGROUND
  Clinical and genetic heterogeneity in monogenetic disorders represents a major diagnostic challenge. Although the presence of particular clinical features may aid in identifying a specific cause in some cases, the majority of patients remain undiagnosed. Here, we investigated the utility of whole-exome sequencing as a diagnostic approach for establishing a molecular diagnosis in a highly heterogeneous group of patients with varied intellectual disability and microcephaly.
  
  
  METHODS
  Whole-exome sequencing was performed in 38 patients, including three sib-pairs, in addition to or in parallel with genetic analyses that were performed during the diagnostic work-up of the study participants.
  
  
  RESULTS
  In ten out of these 35 families (29 %), we found mutations in genes already known to be related to a disorder in which microcephaly is a main feature. Two unrelated patients had mutations in the ASPM gene. In seven other patients we found mutations in RAB3GAP1, RNASEH2B, KIF11, ERCC8, CASK, DYRK1A and BRCA2. In one of the sib-pairs, mutations were found in the RTTN gene. Mutations were present in seven out of our ten families with an established etiological diagnosis with recessive inheritance.
  
  
  CONCLUSIONS
  We demonstrate that whole-exome sequencing is a powerful tool for the diagnostic evaluation of patients with highly heterogeneous neurodevelopmental disorders such as intellectual disability with microcephaly. Our results confirm that autosomal recessive disorders are highly prevalent among patients with microcephaly.
authors: Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands. p.rump@umcg.nl.
authors: Patrick
authors: P
authors: Rump
authors: Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands. o.jazayeri@umcg.nl.
authors: Omid
authors: O
authors: Jazayeri
authors: Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands. k.k.dijk@umcg.nl.
authors: Krista K
authors: KK
authors: van Dijk-Bos
authors: Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands. l.johansson@umcg.nl.|Department of Genetics, University of Groningen, University Medical Centre Groningen, Genomics Coordination Centre, Groningen, The Netherlands. l.johansson@umcg.nl.
authors: Lennart F
authors: LF
authors: Johansson
authors: Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands. a.j.van.essen@umcg.nl.
authors: Anthonie J
authors: AJ
authors: van Essen
authors: Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands. j.b.g.m.verheij@umcg.nl.
authors: Johanna B G M
authors: JB
authors: Verheij
authors: Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands. h.e.veenstra-knol@umcg.nl.
authors: Hermine E
authors: HE
authors: Veenstra-Knol
authors: Department of Clinical Genetics, University of Amsterdam, Academic Medical Centre, Amsterdam, The Netherlands. e.j.w.redeker@amc.uva.nl.
authors: Egbert J W
authors: EJ
authors: Redeker
authors: Department of Clinical Genetics, University of Amsterdam, Academic Medical Centre, Amsterdam, The Netherlands. m.a.mannens@amc.uva.nl.
authors: Marcel M A M
authors: MM
authors: Mannens
authors: Department of Genetics, University of Groningen, University Medical Centre Groningen, Genomics Coordination Centre, Groningen, The Netherlands. m.a.swertz@gmail.com.
authors: Morris A
authors: MA
authors: Swertz
authors: Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands. b.z.alizadeh@umcg.nl.
authors: Behrooz Z
authors: BZ
authors: Alizadeh
authors: Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands. c.m.a.van.ravenswaaij@umcg.nl.
authors: Conny M A
authors: CM
authors: van Ravenswaaij-Arts
authors: Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands. r.j.sinke@umcg.nl.
authors: Richard J
authors: RJ
authors: Sinke
authors: Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands. b.sikkema01@umcg.nl.
authors: Birgit
authors: B
authors: Sikkema-Raddatz
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D059472:Exome / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000150:complications* / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000150:complications* / Q000235:genetics*; D008875:Middle Aged; D017422:Sequence Analysis, DNA / Q000379:methods*; D055815:Young Adult