Mutations affecting the SAND domain of DEAF1 cause intellectual disability with severe speech impairment and behavioral problems

Am J Hum Genet. 2014 May 1;94(5):649-61. doi: 10.1016/j.ajhg.2014.03.013.

Anneke T Vulto-van Silfhout ¹, Shivakumar Rajamanickam ², Philip J Jensik ², Sarah Vergult ³, Nina de Rocker ³, Kathryn J Newhall ⁴, Ramya Raghavan ², Sara N Reardon ², Kelsey Jarrett ², Tara McIntyre ², Joseph Bulinski ², Stacy L Ownby ², Jodi I Huggenvik ², G Stanley McKnight ⁴, Gregory M Rose ⁵, Xiang Cai ², Andy Willaert ³, Christiane Zweier ⁶, Sabine Endele ⁶, Joep de Ligt ¹, Bregje W M van Bon ¹, Dorien Lugtenberg ¹, Petra F de Vries ¹, Joris A Veltman ¹, Hans van Bokhoven ⁷, Han G Brunner ¹, Anita Rauch ⁸, Arjan P M de Brouwer ⁷, Gemma L Carvill ⁹, Alexander Hoischen ¹, Heather C Mefford ⁹, Evan E Eichler ¹⁰, Lisenka E L M Vissers ¹, Björn Menten ³, Michael W Collard ², Bert B A de Vries ¹¹

Affiliations

1 Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
2 Department of Physiology and Center for Integrated Research in Cognitive & Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
3 Center for Medical Genetics, Ghent University, Ghent 9000, Belgium.
4 Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
5 Department of Physiology and Center for Integrated Research in Cognitive & Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA; Department of Anatomy, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
6 Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
7 Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Department of Cognitive Neurosciences, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
8 Institute of Medical Genetics, University of Zurich, 8603 Schwerzenbach-Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich, 8603 Schwerzenbach-Zurich, Switzerland; Zurich Center of Integrative Human Physiology, University of Zurich, 8603 Schwerzenbach-Zurich, Switzerland.
9 Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
10 Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA.
11 Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands. Electronic address: bert.devries@radboudumc.nl.

PMID: 24726472 DOI: 10.1016/j.ajhg.2014.03.013

Abstract

Recently, we identified in two individuals with intellectual disability (ID) different de novo mutations in DEAF1, which encodes a transcription factor with an important role in embryonic development. To ascertain whether these mutations in DEAF1 are causative for the ID phenotype, we performed targeted resequencing of DEAF1 in an additional cohort of over 2,300 individuals with unexplained ID and identified two additional individuals with de novo mutations in this gene. All four individuals had severe ID with severely affected speech development, and three showed severe behavioral problems. DEAF1 is highly expressed in the CNS, especially during early embryonic development. All four mutations were missense mutations affecting the SAND domain of DEAF1. Altered DEAF1 harboring any of the four amino acid changes showed impaired transcriptional regulation of the DEAF1 promoter. Moreover, behavioral studies in mice with a conditional knockout of Deaf1 in the brain showed memory deficits and increased anxiety-like behavior. Our results demonstrate that mutations in DEAF1 cause ID and behavioral problems, most likely as a result of impaired transcriptional regulation by DEAF1.

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