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

Vulto-Van Silfhout AT, Rajamanickam S, Jensik PJ, Vergult S, De Rocker N, Newhall KJ, Raghavan R, Reardon SN, Jarrett K, Mcintyre T, Bulinski J, Ownby SL, Huggenvik JI, Mcknight GS, Rose GM, Cai X, Willaert A, Zweier C, Endele S, De Ligt J, Van Bon BWM, Lugtenberg D, De Vries PF, Veltman JA, Van Bokhoven H, Brunner HG, Rauch A, De Brouwer APM, Carvill GL, Hoischen A, Mefford HC, Eichler EE, Vissers LELM, Menten B, Collard MW, De Vries BBA (2014)

Publication Type: Journal article

Publication year: 2014

Journal

American Journal of Human Genetics Elsevier (Cell Press)

Book Volume: 94

Pages Range: 649-61

Journal Issue: 5

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.

Authors with CRIS profile

Christiane Zweier Lehrstuhl für Humangenetik Sabine Endele Institute of Human Genetics

Involved external institutions

Southern Illinois University Carbondale US United States (USA) (US) Radboud University Nijmegen NL Netherlands (NL) Universiteit Gent (UGent) / Ghent University BE Belgium (BE) University of Washington US United States (USA) (US) University of Zurich / Universität Zürich (UZH) CH Switzerland (CH)

How to cite

APA:

Vulto-Van Silfhout, A.T., Rajamanickam, S., Jensik, P.J., Vergult, S., De Rocker, N., Newhall, K.J.,... De Vries, B.B.A. (2014). Mutations affecting the SAND domain of DEAF1 cause intellectual disability with severe speech impairment and behavioral problems. American Journal of Human Genetics, 94(5), 649-61. https://doi.org/10.1016/j.ajhg.2014.03.013

MLA:

Vulto-Van Silfhout, Anneke T., et al. "Mutations affecting the SAND domain of DEAF1 cause intellectual disability with severe speech impairment and behavioral problems." American Journal of Human Genetics 94.5 (2014): 649-61.

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