De novo variants of DEAF1 cause intellectual disability in six Chinese patients

Chen, Shimeng; Deng, Xingming; Xiong, Juan; He, Fang; Yang, Lifen; Chen, Baiyu; Chen, Chen; Zhang, Ciliu; Yang, Li; Peng, Jing; Yin, Fei

doi:10.1016/j.cca.2021.02.026

Cited by 3 publications

(5 citation statements)

References 30 publications

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“…Regarding the curative effect observation of antiepileptic drugs (AEDs) treatment, hitherto, there have been only two studies with small samples or case series, but their conclusions were opposite. One study included six individuals with VSVS, and the result showed almost all generalized persons (5/6; 83.3%) had no epileptic seizures by the use of valproic acid therapy (1). In contrast, the other study included 10 individuals, which revealed that epilepsies were not well controlled in the overwhelming majority of individuals (9/10;90%) (2).…”

Section: Discussionmentioning

confidence: 99%

“…Owing to the seizures of VSVS being ordinarily generalized, valproic acid could be the first choice in AEDs (1). Chen et al (1) speculated that the interaction between valproic acid and the DEAF1 gene may inhibit neuronal excitation. The difference in the results of the two studies on antiepileptic efficacy may be attributed to the function of different pathogenic variants in the DEAF1 gene leading to different responses to AEDs (1,2).…”

Section: Discussionmentioning

confidence: 99%

“…Chen et al (1) speculated that the interaction between valproic acid and the DEAF1 gene may inhibit neuronal excitation. The difference in the results of the two studies on antiepileptic efficacy may be attributed to the function of different pathogenic variants in the DEAF1 gene leading to different responses to AEDs (1,2). Additionally, because the individuals in the two studies were treated with different AEDs, an accurate assessment was not available.…”

Section: Discussionmentioning

confidence: 99%

“…Vulto-van Silfhout-de Vries syndrome (VSVS; MIM 615828), also known as autosomal dominant mental retardation-24 (MRD24), is an autosomal dominant disorder caused by de novo heterozygous pathogenic variant in DEAF1 gene (1). The major clinical phenotypes of VSVS include different levels (mild to severe) of intellectual disability (ID) and/or global developmental delay (GDD), serious language limitations, motor retardation, autism spectrum disorders (ASD), problems with behaving, somnipathy, and increased pain threshold.…”

Section: Introductionmentioning

confidence: 99%

“…The major clinical phenotypes of VSVS include different levels (mild to severe) of intellectual disability (ID) and/or global developmental delay (GDD), serious language limitations, motor retardation, autism spectrum disorders (ASD), problems with behaving, somnipathy, and increased pain threshold. It is fairly rare with only 11 articles having described the disease and has an unknown incidence (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

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Vulto-van Silfhout-de Vries syndrome caused by de novo variants of DEAF1 gene: a case report and literature review

Zhu,

Jiang

et al. 2023

Front. Neurol.

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Vulto-van Silfhout-de Vries syndrome (VSVS; MIM 615828) is an extremely rare autosomal dominant disorder with unknown incidence. It is always caused by de novo heterozygous pathogenic variants in the DEAF1 gene, which encodes deformed epidermal autoregulatory factor-1 homology. VSVS is characterized by mild to severe intellectual disability (ID) and/or global developmental delay (GDD), seriously limited language expression, behavioral abnormalities, somnipathy, and reduced pain sensitivity. In this study, we present a Chinese boy with moderate GDD and ID, severe expressive language impairment, behavioral issues, autism spectrum disorder (ASD), sleeping dysfunction, high pain threshold, generalized seizures, imbalanced gait, and recurrent respiratory infections as clinical features. A de novo heterozygous pathogenic missense variant was found in the 5th exon of DEAF1 gene, NM_021008.4 c.782G>C (p. Arg261Pro) variant by whole exome sequencing (WES). c.782G>C had not been previously reported in genomic databases and literature. According to the ACMG criteria, this missense variant was considered to be “Likely Pathogenic”. We diagnosed the boy with VSVS both genetically and clinically. At a follow-up of 2.1 years, his seizures were well controlled after valproic acid therapy. In addition, the child’s recurrent respiratory infections improved at 3.5 years of age, which has not been reported in previous individuals. Maybe the recurrent respiratory infections like sleep problems reported in the literature are not permanent but may improve naturally over time. The literature review showed that there were 35 individuals with 28 different de novo pathogenic variants of DEAF1-related VSVS. These variants were mostly missense and the clinical manifestations were similar to our patient. Our study expands the genotypic and phenotypic profiles of de novo DEAF1.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Vulto-van Silfhout-de Vries syndrome caused by de novo variants of DEAF1 gene: a case report and literature review

Zhu,

Jiang

et al. 2023

Front. Neurol.

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Expansion and mechanistic insights into de novo DEAF1 variants in DEAF1-associated neurodevelopmental disorders

McGee

Rajamanickam

Adhikari

et al. 2022

Human Molecular Genetics

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De novo deleterious and heritable biallelic mutations in the DNA binding domain (DBD) of the transcription factor deformed epidermal autoregulatory factor 1 (DEAF1) result in a phenotypic spectrum of disorders termed DEAF1-associated neurodevelopmental disorders (DAND). RNA-sequencing using hippocampal RNA from mice with conditional deletion of Deaf1 in the central nervous system indicate that loss of Deaf1 activity results in the altered expression of genes involved in neuronal function, dendritic spine maintenance, development, and activity, with reduced dendritic spines in hippocampal regions. Since DEAF1 is not a dosage-sensitive gene, we assessed the dominant negative activity of previously identified de novo variants and a heritable recessive DEAF1 variant on selected DEAF1-regulated genes in 2 different cell models. While no altered gene expression was observed in cells over-expressing the recessive heritable variant, the gene expression profiles of cells over-expressing de novo variants resulted in similar gene expression changes as observed in CRISPR-Cas9-mediated DEAF1-deleted cells. Altered expression of DEAF1-regulated genes was rescued by exogenous expression of WT-DEAF1 but not by de novo variants in cells lacking endogenous DEAF1. De novo heterozygous variants within the DBD of DEAF1 were identified in 10 individuals with a phenotypic spectrum including autism spectrum disorder, developmental delays, sleep disturbance, high pain tolerance, and mild dysmorphic features. Functional assays demonstrate these variants alter DEAF1 transcriptional activity. Taken together, this study expands the clinical phenotypic spectrum of individuals with DAND, furthers our understanding of potential roles of DEAF1 on neuronal function, and demonstrates dominant negative activity of identified de novo variants.

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Theoretical Studies of DNA Microarray Present Potential Molecular and Cellular Interconnectivity of Signaling Pathways in Immune System Dysregulation

Garcia,

Tayo

2024

Genes

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Autoimmunity is defined as the inability to regulate immunological activities in the body, especially in response to external triggers, leading to the attack of the tissues and organs of the host. Outcomes include the onset of autoimmune diseases whose effects are primarily due to dysregulated immune responses. In past years, there have been cases that show an increased susceptibility to other autoimmune disorders in patients who are already experiencing the same type of disease. Research in this field has started analyzing the potential molecular and cellular causes of this interconnectedness, bearing in mind the possibility of advancing drugs and therapies for the treatment of autoimmunity. With that, this study aimed to determine the correlation of four autoimmune diseases, which are type 1 diabetes (T1D), psoriasis (PSR), systemic sclerosis (SSc), and systemic lupus erythematosus (SLE), by identifying highly preserved co-expressed genes among datasets using WGCNA. Functional annotation was then employed to characterize these sets of genes based on their systemic relationship as a whole to elucidate the biological processes, cellular components, and molecular functions of the pathways they are involved in. Lastly, drug repurposing analysis was performed to screen candidate drugs for repositioning that could regulate the abnormal expression of genes among the diseases. A total of thirteen modules were obtained from the analysis, the majority of which were associated with transcriptional, post-transcriptional, and post-translational modification processes. Also, the evaluation based on KEGG suggested the possible role of TH17 differentiation in the simultaneous onset of the four diseases. Furthermore, clomiphene was the top drug candidate for regulating overexpressed hub genes; meanwhile, prilocaine was the top drug for regulating under-expressed hub genes. This study was geared towards utilizing transcriptomics approaches for the assessment of microarray data, which is different from the use of traditional genomic analyses. Such a research design for investigating correlations among autoimmune diseases may be the first of its kind.

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De novo variants of DEAF1 cause intellectual disability in six Chinese patients

Cited by 3 publications

References 30 publications

Vulto-van Silfhout-de Vries syndrome caused by de novo variants of DEAF1 gene: a case report and literature review

Vulto-van Silfhout-de Vries syndrome caused by de novo variants of DEAF1 gene: a case report and literature review

Expansion and mechanistic insights into de novo DEAF1 variants in DEAF1-associated neurodevelopmental disorders

Theoretical Studies of DNA Microarray Present Potential Molecular and Cellular Interconnectivity of Signaling Pathways in Immune System Dysregulation

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