SPEN

Chr 1AD

spen family transcriptional repressor

Also known as: HIAA0929, MINT, RATARS, RBM15C, SHARP

NCBI Gene: 23013 ENSG00000065526 UniProt: Q96T58 OMIM: 613484

This gene encodes a transcriptional repressor that regulates key developmental pathways including Notch signaling and serves as a nuclear matrix platform organizing transcriptional responses. Mutations cause Radio-Tartaglia syndrome, an autosomal dominant disorder characterized by intellectual disability, distinctive facial features, and skeletal abnormalities. The gene is highly constrained against loss-of-function variation (pLI=1, LOEUF=0.071), indicating that complete loss of protein function is likely incompatible with normal development.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a hormone inducible transcriptional repressor. Repression of transcription by this gene product can occur through interactions with other repressors, by the recruitment of proteins involved in histone deacetylation, or through sequestration of transcriptional activators. The product of this gene contains a carboxy-terminal domain that permits binding to other corepressor proteins. This domain also permits interaction with members of the NuRD complex, a nucleosome remodeling protein complex that contains deacetylase activity. In addition, this repressor contains several RNA recognition motifs that confer binding to a steroid receptor RNA coactivator; this binding can modulate the activity of both liganded and nonliganded steroid receptors. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.071 OMIM phenotype

Clinical Summary— SPEN

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Gene-Disease Validity (ClinGen)

Radio-Tartaglia syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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GeneReview available — SPEN

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.07LOEUF

pLI 1.000

Z-score 10.20

OE 0.03 (0.01–0.07)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

2.89Z-score

OE missense 0.82 (0.79–0.85)

1697 obs / 2067.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.03 (0.01–0.07)

0≤0.351.4

Missense OE?0.82 (0.79–0.85)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 4 / 129.0Missense obs/exp: 1697 / 2067.2Syn Z: -0.32

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSPEN-related developmental disorderLOFAD

This gene — mechanism propensity

0.12100th %ile

GOF

0.15100th %ile

LOF

0.92top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · LOEUF 0.07 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFSPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females.1

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

References