De novo and biallelic DEAF1 variants cause a phenotypic spectrum

Maria J. Nabais Sá, Philip J. Jensik, Stacey R. McGee, Michael J. Parker, Nayana Lahiri, Evan P. McNeil, Hester Y. Kroes, Randi J. Hagerman, Rachel E. Harrison, Tara Montgomery, Miranda Splitt, Elizabeth E. Palmer, Rani K. Sachdev, Heather C. Mefford, Abbey A. Scott, Julian A. Martinez-Agosto, Rüdiger Lorenz, Naama Orenstein, Jonathan N. Berg, Jeanne AmielDelphine Heron, Boris Keren, Jan-Maarten Cobben, Leonie A. Menke, Elysa J. Marco, John M. Graham, Tyler Mark Pierson, Ehsan Ghayoor Karimiani, Reza Maroofian, M. Chiara Manzini, Edmund S. Cauley, Roberto Colombo, Sylvie Odent, Christele Dubourg, Chanika Phornphutkul, Arjan P. M. de Brouwer, Bert B. A. de Vries (Lead / Corresponding author), Anneke T Vulto-vanSilfhout

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)


Purpose: To investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro.

Methods: We assembled a cohort of 23 patients with de novo and biallelic DEAF1 variants, described the genotype-phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs.

Results: The proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p < 0.0001).

Conclusion: We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients.

Original languageEnglish
Pages (from-to)2059-2069
Number of pages11
JournalGenetics in Medicine
Issue number9
Early online date29 Mar 2019
Publication statusPublished - Sept 2019


  • DEAF1
  • genotype
  • intellectual disability
  • neurodevelopmental disorder
  • phenotype

ASJC Scopus subject areas

  • Genetics(clinical)


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