title: Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing.
abstract: BACKGROUND
  Intellectual disability (ID) is a common neurodevelopmental disorder affecting 1-3% of the general population. Mutations in more than 10% of all human genes are considered to be involved in this disorder, although the majority of these genes are still unknown.
  
  
  OBJECTIVE
  We investigated 19 small non-consanguineous families with two to five affected siblings in order to identify pathogenic gene variants in known, novel and potential ID candidate genes. Non-consanguineous families have been largely ignored in gene identification studies as small family size precludes prior mapping of the genetic defect.
  
  
  RESULTS
  Using exome sequencing, we identified pathogenic mutations in three genes, DDHD2, SLC6A8, and SLC9A6, of which the latter two have previously been implicated in X-linked ID phenotypes. In addition, we identified potentially pathogenic mutations in BCORL1 on the X-chromosome and in MCM3AP, PTPRT, SYNE1, and ZNF528 on autosomes.
  
  
  CONCLUSIONS
  We show that potentially pathogenic gene variants can be identified in small, non-consanguineous families with as few as two affected siblings, thus emphasising their value in the identification of syndromic and non-syndromic ID genes.
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Janneke H M
authors.initials: JH
authors.lastname: Schuurs-Hoeijmakers
authors.forename: Anneke T
authors.initials: AT
authors.lastname: Vulto-van Silfhout
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
authors.forename: Ilse I G M
authors.initials: II
authors.lastname: van de Vondervoort
authors.forename: Bregje W M
authors.initials: BW
authors.lastname: van Bon
authors.forename: Joep
authors.initials: J
authors.lastname: de Ligt
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.forename: Jayne Y
authors.initials: JY
authors.lastname: Hehir-Kwa
authors.forename: Kornelia
authors.initials: K
authors.lastname: Neveling
authors.forename: Marisol
authors.initials: M
authors.lastname: del Rosario
authors.forename: Gausiya
authors.initials: G
authors.lastname: Hira
authors.forename: Santina
authors.initials: S
authors.lastname: Reitano
authors.forename: Aurelio
authors.initials: A
authors.lastname: Vitello
authors.forename: Pinella
authors.initials: P
authors.lastname: Failla
authors.forename: Donatella
authors.initials: D
authors.lastname: Greco
authors.forename: Marco
authors.initials: M
authors.lastname: Fichera
authors.forename: Ornella
authors.initials: O
authors.lastname: Galesi
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
authors.forename: Marie T
authors.initials: MT
authors.lastname: Greally
authors.forename: Charlotte W
authors.initials: CW
authors.lastname: Ockeloen
authors.forename: Marjolein H
authors.initials: MH
authors.lastname: Willemsen
authors.forename: Ernie M H F
authors.initials: EM
authors.lastname: Bongers
authors.forename: Irene M
authors.initials: IM
authors.lastname: Janssen
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.forename: Corrado
authors.initials: C
authors.lastname: Romano
authors.forename: Michèl A
authors.initials: MA
authors.lastname: Willemsen
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Bert B A
authors.initials: BB
authors.lastname: de Vries
authors.forename: Arjan P M
authors.initials: AP
authors.lastname: de Brouwer
mesh_terms: D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics*; D005190:Family; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree
keywords: Genetics