De novo and biallelic DEAF1 variants cause a phenotypic spectrum

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.

Diencephalic and Neuropeptidergic Dysfunction in Zebrafish with Autism Risk Mutations

“…S16 ). Observed gene expression differences from the three lines matched published literature results for orthologs of DEAF1 , EIF4G3 , UBE2M , and RAC3 ( 6 , 52 ) ( Fig. 4A ).…”

“…As Deaf1 is a transcription factor, it is expected to produce phenotypes by directly modulating expression of its target genes. The missense mutations are predicted to impact DNA-binding or transcriptional activity but could result in more complex outcomes than truncating mutations through retained interactions with binding partners ( 6 , 52 ).…”

Autism spectrum disorder trios from consanguineous populations are enriched for rare biallelic variants, identifying 32 new candidate genes

“…A number of the ID genes identified here among ASD trios have also previously been reported for ASD or ASD-like features, e.g. CC2D1A (Manzini et al, 2014;Sener et al, 2020), VPS13B (Yu et al, 2013), DEAF1 (Nabais Sá et al, 2019), ZNF335 (Wu et al, 2018), ZNF292 (Guo et al, 2018;Mirzaa et al, 2019;Wang et al, 2016), MYT1L (Coursimault et al, 2021;, SCN2A (Jiang et al, 2013;Sanders et al, 2012;Weiss et al, 2003), and PLXNA3 (Steele et al, 2021;Wang et al, 2021). Of the candidate genes identified here, MSSNG, SFARI, and other datasets provide putative support (however it is not possible to determine whether two reported mutations in the same gene are on the same alleles or not, unless occurring within the same sequence read) for the biallelic genes DNAH8, SCN10A, CLCA4, ANO10, WDR90 (Supplementary Table S1), and for de novo/dominant genes NCL, SLAMF7, ADGRF2, DGKZ, ATP2B1, CBFA2T3, RETN, and PPIL2 (Supplementary Table S2).…”

“…We identified mutations in several genes that have been previously reported to be associated with autosomal recessive non-syndromic ID, such as TECPR2 (Anazi et al, 2017) , MTHFR (Reuter et al, 2017) , MADD (Anazi et al, 2017), BTN3A2 (Anazi et al, 2017), LINS1 (Najmabadi et al, 2011) , CC2D1A (MIM 608443; MRT3; (Basel-Vanagaite et al, 2006)Basel-Vanagaite et al, 2006, RSRC1 (Maddirevula et al, 2018;Perez et al, 2018) and ZNF335 (Hu et al, 2018), and a number known for syndromic or metabolic forms of autosomal recessive ID, including VPS13B (Cohen syndrome), AGA (aspartylglucosaminuria), ASL (arginosuccinic aciduria), HTRA2 (3-methylglutaconic aciduria) ASPA (aspartoacylase deficiency/Canavan disease), and MED25 (Basel-Vanagaite-Smirin-Yosef syndrome). CC2D1A, VPS13B, and DEAF1 have also previously been associated with ASD or autistic features (Douzgou and Petersen, 2011;Manzini et al, 2014;Nabais Sá et al, 2019). Biallelic mutations in DEAF1 are known to cause neurodevelopmental disorder with hypotonia, impaired expressive language, with or without seizures (MIM 617171).…”

PhenomAD-NDD: the Phenomics Aggregation Database of comorbidities in 51,227 pediatric individuals with NeuroDevelopmental Disorders

“…Of these, 59 (2%) reach statistical significance after Bonferroni correction, indicating that these are more prevalent in the general NDD population than in the genetic syndrome. An example of such a clinical feature is feeding difficulties for disorder associated with heterozygous pathogenic variants in DEAF1 (Vulto-van Silfout-de Vries syndrome, OMIM #615828 [28]). The syndrome is characterized by delayed development, behavioral abnormalities, hypotonia and seizures, with a wide range of symptoms described.…”