GLI2

Chr 2AD

GLI family zinc finger 2

Also known as: CJS, HPE9, PHS2, THP1, THP2

NCBI Gene: 2736 ENSG00000074047 UniProt: P10070 OMIM: 165230

GLI2 encodes a zinc finger transcription factor that regulates gene expression in the sonic hedgehog signaling pathway, which is essential for normal embryonic development. Mutations cause autosomal dominant conditions including Culler-Jones syndrome, holoprosencephaly 9, Greig cephalopolysyndactyly syndrome, and Pallister-Hall syndrome, affecting brain development and limb formation. The gene is highly constrained against loss-of-function variants (pLI 0.97), reflecting its critical developmental role.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein which belongs to the C2H2-type zinc finger protein subclass of the Gli family. Members of this subclass are characterized as transcription factors which bind DNA through zinc finger motifs. These motifs contain conserved H-C links. Gli family zinc finger proteins are mediators of Sonic hedgehog (Shh) signaling and they are implicated as potent oncogenes in the embryonal carcinoma cell. The protein encoded by this gene localizes to the cytoplasm and activates patched Drosophila homolog (PTCH) gene expression. It is also thought to play a role during embryogenesis. The encoded protein is associated with several phenotypes- Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, preaxial polydactyly type IV, postaxial polydactyly types A1 and B. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.312 OMIM phenotypes

Clinical Summary— GLI2

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.31LOEUF

pLI 0.973

Z-score 5.44

OE 0.18 (0.11–0.31)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

0.82Z-score

OE missense 0.93 (0.88–0.98)

896 obs / 967.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.18 (0.11–0.31)

0≤0.351.4

Missense OE?0.93 (0.88–0.98)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 9 / 50.8Missense obs/exp: 896 / 967.5Syn Z: 0.74

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveGLI2-related holoprosencephalyLOFAD

This gene — mechanism propensity

0.3991th %ile

GOF

0.2497th %ile

LOF

0.81top 5%

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.

LOFprediction above median · 1 literature citation · LOEUF 0.31 · ClinGen HI: Sufficient evidence for dosage pathogenicity

DN1 literature citation

Literature Evidence

DNFunctional assays confirmed the pathogenicity of the identified variant and revealed a dominant-negative effect of mutant GLI2 on Hedgehog signalling.1

LOFDiagnostic exome sequencing identifies GLI2 haploinsufficiency and chromosome 20 uniparental disomy in a patient with developmental anomalies.2

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

References