DEAF1 – Vulto-van Silfhout-de Vries Syndrome

Vulto-van Silfhout-de Vries Syndrome (VSVS; intellectual disability, autosomal dominant 24) is a rare neurodevelopmental disorder characterized by mild to severe intellectual disability, global developmental delay, impaired speech, autistic features, and seizures ([HP:0001263], [HP:0002197]). All reported cases arise from heterozygous de novo variants in the transcription factor gene DEAF1 (Gene Symbol; Disease Name).

Genetic evidence for this association is robust (Strong). To date, 35 unrelated probands with 28 distinct de novo missense variants have been described, each with consistent neurodevelopmental phenotypes and no familial inheritance ([PMID:38073621]). Individual case reports include a 23-year-old male with c.662C>T (p.Ser221Leu) presenting with autism spectrum disorder, growth retardation, and seizures ([PMID:36010237]), and a Chinese boy harboring c.782G>C (p.Arg261Pro) who exhibited moderate global developmental delay, generalized seizures, and recurrent respiratory infections ([PMID:38073621]).

The variant spectrum is dominated by missense changes clustering in the SAND and DNA-binding domains of DEAF1, with no recurrent or founder alleles reported. Loss-of-function variants are rare, and no hypomorphic or deep-intronic alleles have been implicated.

Functional studies provide moderate evidence of pathogenicity. Luciferase reporter assays, electrophoretic mobility shift assays, and immunofluorescence analyses demonstrated that several de novo missense variants (e.g., c.634G>A (p.Gly212Ser)) markedly reduce transcriptional repression activity and DNA-binding affinity ([PMID:28940898]).

Mechanistic investigations in cellular models and conditional Deaf1 knockout mice reveal a dominant-negative effect of de novo variants, leading to dysregulated expression of neuronal genes, reduced dendritic spine density, and failure of exogenous wild-type DEAF1 to rescue gene expression changes ([PMID:35981081]).

In summary, de novo heterozygous DEAF1 variants cause VSVS through a dominant-negative mechanism that impairs transcriptional regulation, resulting in a consistent neurodevelopmental phenotype. This strong gene-disease association supports inclusion of DEAF1 in diagnostic panels for intellectual disability and guides variant interpretation, with functional assays recommended for novel missense changes.

References

• Diagnostics (Basel, Switzerland) • 2022 • A Unique Observation of a Patient with Vulto-van Silfhout-de Vries Syndrome PMID:36010237
• Frontiers in Neurology • 2023 • Vulto-van Silfhout-de Vries syndrome caused by de novo variants of DEAF1 gene: a case report and literature review PMID:38073621
• Human Mutation • 2017 • Functional analysis of novel DEAF1 variants identified through clinical exome sequencing expands DEAF1-associated neurodevelopmental disorder (DAND) phenotype PMID:28940898
• Genetics in Medicine • 2019 • De novo and biallelic DEAF1 variants cause a phenotypic spectrum PMID:30923367
• Human Molecular Genetics • 2023 • Expansion and mechanistic insights into de novo DEAF1 variants in DEAF1-associated neurodevelopmental disorders PMID:35981081

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