OTX2

Chr 14AD

orthodenticle homeobox 2

Also known as: CPHD6, MCOPS5

NCBI Gene: 5015 ENSG00000165588 UniProt: P32243 OMIM: 600037

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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the bicoid subfamily of homeodomain-containing transcription factors. The encoded protein acts as a transcription factor and plays a role in brain, craniofacial, and sensory organ development. The encoded protein also influences the proliferation and differentiation of dopaminergic neuronal progenitor cells during mitosis. Mutations in this gene cause syndromic microphthalmia 5 (MCOPS5) and combined pituitary hormone deficiency 6 (CPHD6). This gene is also suspected of having an oncogenic role in medulloblastoma. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Pseudogenes of this gene are known to exist on chromosomes two and nine. [provided by RefSeq, Jul 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.383 OMIM phenotypes

Clinical Summary— OTX2

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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.

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ClinVar Variants

64 unique Pathogenic / Likely Pathogenic· 161 VUS of 313 total submissions

Explore recent and relevant literature in Research Assistant →

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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 OE?0.08 (0.03–0.38)

0≤0.351.4

Missense OE?0.77 (0.66–0.89)

0≤0.61.4

Synonymous OE?1.02

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

This gene — mechanism propensity

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 · 77% of P/LP variants are LoF · LOEUF 0.38 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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.1

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.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

ClinVar Variant Classifications

313 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic47

Likely Pathogenic17

VUS161

Likely Benign69

Benign6

Conflicting13

Pathogenic

Likely Pathogenic

161

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	40	3	4	0	47
Likely Pathogenic	9	7	1	0	17
VUS	6	142	12	1	161
Likely Benign	0	4	10	55	69
Benign	0	0	6	0	6
Conflicting	—				13
Total	55	156	33	56	313

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

14 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap OTX2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →