Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing

  • J Med Genet. 2013 Dec;50(12):802-11. doi: 10.1136/jmedgenet-2013-101644.
Janneke H M Schuurs-Hoeijmakers  1 ,  Anneke T Vulto-van Silfhout ,  Lisenka E L M Vissers ,  Ilse I G M van de Vondervoort ,  Bregje W M van Bon ,  Joep de Ligt ,  Christian Gilissen ,  Jayne Y Hehir-Kwa ,  Kornelia Neveling ,  Marisol del Rosario ,  Gausiya Hira ,  Santina Reitano ,  Aurelio Vitello ,  Pinella Failla ,  Donatella Greco ,  Marco Fichera ,  Ornella Galesi ,  Tjitske Kleefstra ,  Marie T Greally ,  Charlotte W Ockeloen ,  Marjolein H Willemsen ,  Ernie M H F Bongers ,  Irene M Janssen ,  Rolph Pfundt ,  Joris A Veltman ,  Corrado Romano ,  Michèl A Willemsen ,  Hans van Bokhoven ,  Han G Brunner ,  Bert B A de Vries ,  Arjan P M de Brouwer
Affiliations
  • 1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
PMID: 24123876 DOI: 10.1136/jmedgenet-2013-101644
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.

Objectives: 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.

Methods and 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.

Keywords
Genetics.