DEAF1

Chr 11ARAD

DEAF1 transcription factor

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

Transcription factor that binds to sequence with multiple copies of 5'-TTC[CG]G-3' present in its own promoter and that of the HNRPA2B1 gene. Down-regulates transcription of these genes. Binds to the retinoic acid response element (RARE) 5'-AGGGTTCACCGAAAGTTCA-3'. Activates the proenkephalin gene independently of promoter binding, probably through protein-protein interaction. When secreted, behaves as an inhibitor of cell proliferation, by arresting cells in the G0 or G1 phase. Required for neural tube closure and skeletal patterning. Regulates epithelial cell proliferation and side-branching in the mammary gland. Controls the expression of peripheral tissue antigens in pancreatic lymph nodes. Isoform 1 displays greater transcriptional activity than isoform 4. Isoform 4 may inhibit transcriptional activity of isoform 1 by interacting with isoform 1 and retaining it in the cytoplasm. Transcriptional activator of EIF4G3

OMIM ResearchGenerating clinical summary…

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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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

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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 OE?0.41 (0.25–0.70)

0≤0.351.4

Missense OE?0.77 (0.69–0.85)

0≤0.61.4

Synonymous OE?1.06

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

This gene — mechanism propensity

0.5082th %ile

GOF

0.3590th %ile

LOF

0.52top 25%

The Badonyi & Marsh model scores loss-of-function highest, but genomic evidence most strongly supports dominant-negative as the primary mechanism.

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 1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References