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Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing
  1. Janneke H M Schuurs-Hoeijmakers1,2,3,
  2. Anneke T Vulto-van Silfhout1,2,4,
  3. Lisenka E L M Vissers1,2,3,
  4. Ilse I G M van de Vondervoort1,
  5. Bregje W M van Bon1,
  6. Joep de Ligt1,2,3,
  7. Christian Gilissen1,2,3,
  8. Jayne Y Hehir-Kwa1,2,3,
  9. Kornelia Neveling1,2,3,
  10. Marisol del Rosario1,
  11. Gausiya Hira1,
  12. Santina Reitano4,
  13. Aurelio Vitello4,
  14. Pinella Failla4,
  15. Donatella Greco4,
  16. Marco Fichera4,5,
  17. Ornella Galesi4,
  18. Tjitske Kleefstra1,2,3,
  19. Marie T Greally6,
  20. Charlotte W Ockeloen1,
  21. Marjolein H Willemsen1,2,3,
  22. Ernie M H F Bongers1,2,3,
  23. Irene M Janssen1,
  24. Rolph Pfundt1,
  25. Joris A Veltman1,2,3,
  26. Corrado Romano4,
  27. Michèl A Willemsen7,8,
  28. Hans van Bokhoven1,3,8,
  29. Han G Brunner1,2,3,
  30. Bert B A de Vries1,2,8,
  31. Arjan P M de Brouwer1,3,8
  1. 1Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  2. 2Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  3. 3Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  4. 4Unit of Pediatrics and Medical Genetics, Unit of Neurology, Laboratory of Medical Genetics IRCCS Associazione Oasi Maria Santissima, Troina, Italy
  5. 5Department of Medical Genetics, University of Catania, Catania, Italy
  6. 6National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland
  7. 7Departments of Pediatric Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  8. 8Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  1. Correspondence to Dr Bert B A de Vries, Department of Human Genetics 836, Radboud University Nijmegen Medical Centre, PO Box 9101, Nijmegen NL-6500 HB, The Netherlands; B.devries{at}


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.

  • Genetics

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