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De novo and biallelic DEAF1 variants cause a phenotypic spectrum

M.J. Nabais Sá 1 P.J. Jensik 2 S.R. Mcgee 2 M.J. Parker 3 N. Lahiri 4 E.P. Mcneil 5 H.Y. Kroes 6 R.J. Hagerman 7 R.E. Harrison 8 T. Montgomery 9 M. Splitt 9 E.E. Palmer 10 R.K. Sachdev 10 H.C. Mefford 11 A.A. Scott 11 J.A. Martinez-Agosto 12 R. Lorenz N. Orenstein 13 J.N. Berg 14 J. Amiel 15 D. Heron 16 B. Keren 16 J.-M. Cobben 17 L.A. Menke 17 E.J. Marco J.M. Graham 18 T.M. Pierson 18 E.G. Karimiani 4 R. Maroofian 4 M.C. Manzini 19 E.S. Cauley 19 R. Colombo 20 S. Odent 21 C. Dubourg 22 C. Phornphutkul 23 A.P.M. de Brouwer 1 B.B.A. de Vries 1 A.T. Vulto-Vansilfhout 1
Abstract : 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. © 2019, American College of Medical Genetics and Genomics.
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Submitted on : Friday, May 17, 2019 - 12:05:51 PM
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M.J. Nabais Sá, P.J. Jensik, S.R. Mcgee, M.J. Parker, N. Lahiri, et al.. De novo and biallelic DEAF1 variants cause a phenotypic spectrum. Genetics in Medicine, Nature Publishing Group, 2019, 21 (9), pp.2059-2069. ⟨10.1038/s41436-019-0473-6⟩. ⟨hal-02132596⟩



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