Lookup NU author(s): Dr Tara Montgomery,
Dr Miranda Splitt,
Dr Arjan De Brouwer
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© 2019, American College of Medical Genetics and Genomics. 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.
Author(s): Nabais Sa MJ, Jensik PJ, McGee SR, Parker MJ, Lahiri N, McNeil EP, Kroes HY, Hagerman RJ, Harrison RE, Montgomery T, Splitt M, Palmer EE, Sachdev RK, Mefford HC, Scott AA, Martinez-Agosto JA, Lorenz R, Orenstein N, Berg JN, Amiel J, Heron D, Keren B, Cobben J-M, Menke LA, Marco EJ, Graham JM, Pierson TM, Karimiani EG, Maroofian R, Manzini MC, Cauley ES, Colombo R, Odent S, Dubourg C, Phornphutkul C, de Brouwer APM, de Vries BBA, Vulto-vanSilfhout AT
Publication type: Article
Publication status: Published
Journal: Genetics in Medicine
Pages: Epub ahead of print
Online publication date: 29/03/2019
Acceptance date: 15/02/2019
ISSN (print): 1098-3600
ISSN (electronic): 1530-0366
Publisher: Nature Publishing Group
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