OTX2

Chr 14AD

orthodenticle homeobox 2

Also known as: CPHD6, MCOPS5

NCBI Gene: 5015 ENSG00000165588 UniProt: P32243

This gene encodes a homeodomain transcription factor that regulates brain, craniofacial, and sensory organ development and influences dopaminergic neuronal progenitor cell proliferation and differentiation. Mutations cause autosomal dominant syndromic microphthalmia 5, combined pituitary hormone deficiency 6, and early-onset retinal dystrophy with or without pituitary dysfunction through loss-of-function mechanisms. The protein is highly intolerant to loss-of-function variants, consistent with its critical role in neurodevelopment.

Summary from RefSeq, OMIM, UniProt, Mechanism

Primary Disease Associations & Inheritance

Microphthalmia, syndromic 5MIM #610125

Pituitary hormone deficiency, combined, 6MIM #613986

Retinal dystrophy, early-onset, with or without pituitary dysfunctionMIM #610125

Active trials

Pubs (1 yr)

P/LP submissions

13%

P/LP missense

0.38

LOEUF

LOF

Mechanism· G2P

Clinical Summary— OTX2

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.92). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

78 unique Pathogenic / Likely Pathogenic· 161 VUS of 325 total submissions

📖

GeneReview available — OTX2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.38LOEUF

pLI 0.923

Z-score 3.03

OE 0.08 (0.03–0.38)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

1.05Z-score

OE missense 0.77 (0.66–0.89)

123 obs / 160.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.08 (0.03–0.38)

0≤0.351.4

Missense OE0.77 (0.66–0.89)

0≤0.61.4

Synonymous OE1.02

0≤1.21.6

LoF obs/exp: 1 / 12.6Missense obs/exp: 123 / 160.3Syn Z: -0.10

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveOTX2-related syndromic microphthalmiaLOFAD

0.5772th %ile

GOF

0.2895th %ile

LOF

0.85top 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 · 40% of P/LP variants are LoF · LOEUF 0.38

DN1 literature citation

Literature Evidence

DNWe describe a novel missense heterozygous OTX2 mutation that acts as a dominant negative inhibitor of target gene expression in a patient with CPHD, pituitary malformation, and optic nerve hypoplasia.PMID:22715480

LOFOur findings suggest a role for OTX2 dosage sensitivity in human craniofacial development and raise the possibility of a shared etiology between a subtype of hemifacial microsomia and medulloblastoma.PMID:24816892

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