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…

Primary Disease Associations & Inheritance

Microphthalmia, syndromic 5MIM #610125

Pituitary hormone deficiency, combined, 6MIM #613986

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

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Microphthalmia, syndromic 5; Pituitary hormone deficiency, combined (+1); no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.38

LOEUF

LOF

Mechanism· G2P

📖

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

Background carrier burden — how many people carry a rare variant somewhere in OTX2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 230

320 rare PASS variants

Rare truncating (LoF)

1 in 24,000

11 rare PASS variants

Rare synonymous (reference)

1 in 240

143 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for OTX2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 220	1 in 46,000
South Asian	~43k	1 in 390	1 in 4,300
Remaining (unassigned)	~30k	1 in 190	none seen
European (Finnish)	~27k	1 in 1,100	≈ 1 in 8,900
Admixed American	~22k	1 in 290	1 in 4,500
African / African American	~21k	1 in 260	none seen
East Asian	~20k	1 in 320	none seen
Ashkenazi Jewish	~13k	1 in 590	none seen
Middle Eastern	~2,884	1 in 290	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 3 coding exons well covered in gnomAD exomes and genomes.? see exons ↓