DEAF1

Chr 11ARAD

DEAF1 transcription factor

Also known as: MRD24, NEDHELS, NUDR, SPN, VSVS, ZMYND5

NCBI Gene: 10522 ENSG00000177030 UniProt: O75398 OMIM: 602635

The protein functions as a transcriptional regulator with a zinc finger domain that binds to its own promoter and target gene promoters to control embryonic development. Mutations cause neurodevelopmental disorder with hypotonia, impaired expressive language, and with or without seizures, as well as Vulto-van Silfout-de Vries syndrome, following both autosomal dominant and autosomal recessive inheritance patterns. The pathogenic mechanism involves disrupted transcriptional regulation during critical developmental periods.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismAR/ADLOEUF 0.702 OMIM phenotypes

Clinical Summary— DEAF1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

30 unique Pathogenic / Likely Pathogenic· 162 VUS of 300 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

0.70LOEUF

pLI 0.000

Z-score 2.69

OE 0.41 (0.25–0.70)

Tolerant

Typical tolerance to LoF variation

Missense Constraint

1.50Z-score

OE missense 0.77 (0.69–0.85)

251 obs / 327.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.41 (0.25–0.70)

0≤0.351.4

Missense OE0.77 (0.69–0.85)

0≤0.61.4

Synonymous OE1.06

0≤1.21.6

LoF obs/exp: 10 / 24.3Missense obs/exp: 251 / 327.2Syn Z: -0.54

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongDEAF1-related autism, intellectual disability, basal ganglia dysfunction and epilepsyLOFAR

definitiveDEAF1-related intellectual developmental disorderDNAD

0.5082th %ile

GOF

0.3590th %ile

LOF

0.52top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF40% of P/LP variants are LoF

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNTherefore, a more likely mechanism explaining the consequences of these DEAF1 mutations might be a dominant-negative effect. Data that support this hypothesis are that all of the altered forms of DEAF1 were able to interact with a cytoplasmically localized DEAF1 and relocalize it to the nucleus and PMID:24726472

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.