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

Janneke H M Schuurs-Hoeijmakers, 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. OckeloenMarjolein 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

Research output: Contribution to journalArticlepeer-review


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. Nonconsanguineous 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.

Original languageEnglish
Pages (from-to)802-811
Number of pages10
JournalJournal of Medical Genetics
Issue number12
Publication statusPublished - 2013

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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