OTX2

orthodenticle homeobox 2, the group of PRD class homeoboxes and pseudogenes

Basic information

Region (hg38): 14:56799904-56816693

Links

ENSG00000165588 ∙ NCBI:5015 ∙ OMIM:600037 ∙ HGNC:8522 ∙ Uniprot:P32243 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• syndromic microphthalmia type 5 (Definitive), mode of inheritance: AD
• syndromic microphthalmia type 5 (Strong), mode of inheritance: AD
• pituitary hormone deficiency, combined, 6 (Moderate), mode of inheritance: AD
• syndromic microphthalmia type 5 (Moderate), mode of inheritance: AD
• septooptic dysplasia (Supportive), mode of inheritance: AD
• isolated anophthalmia-microphthalmia syndrome (Supportive), mode of inheritance: AD
• combined pituitary hormone deficiencies, genetic form (Supportive), mode of inheritance: AD
• patterned macular dystrophy (Supportive), mode of inheritance: AD
• syndromic microphthalmia type 5 (Supportive), mode of inheritance: AD
• syndromic microphthalmia type 5 (Strong), mode of inheritance: AD
• pituitary hormone deficiency, combined, 6 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Pituitary hormone deficiency, combined 6; Microphthalmia, syndromic 5; Retinal dystrophy, early-onset, and pituitary dysfunction	AD	Endocrine; Genitourinary	Hormone replacement therapy can be effective, as individuals may have multiple pituitary insufficiency (eg, manifesting with hypothyroidism, growth hormone, gonadotropin, and cortisol deficiency)	Endocrine; Genitourinary; Neurologic; Ophthalmologic	15846561; 18628516; 18728160; 18781617; 19956411; 18854396; 19965921; 20396904; 20486942; 20494911; 21353197; 22198066; 24859618; 25293953; 25589041

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the OTX2 gene.

• Anophthalmia-microphthalmia syndrome (129 variants)
• not provided (46 variants)
• Syndromic microphthalmia type 5 (36 variants)
• Pituitary hormone deficiency, combined, 6 (31 variants)
• OTX2-Related Syndromic Microphthalmia (18 variants)
• Retinal dystrophy (18 variants)
• Syndromic Microphthalmia, Dominant (15 variants)
• Inborn genetic diseases (13 variants)
• not specified (6 variants)
• Combined Pituitary Hormone Deficiency, Dominant (4 variants)
• Anophthalmia (2 variants)
• 46,XY partial gonadal dysgenesis (1 variants)
• OTX2-related disorder (1 variants)
• OTX2-related condition (1 variants)
• Microcephaly (1 variants)
• Pituitary hormone deficiency, combined, 6;Syndromic microphthalmia type 5 (1 variants)
• 9 conditions (1 variants)
• Leber congenital amaurosis (1 variants)
• OTX2-related disorders (1 variants)
• Syndromic microphthalmia type 5;Pituitary hormone deficiency, combined, 6 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the OTX2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	33	1	35
missense		4	90	1		95
nonsense	11	2	3			16
start loss						0
frameshift	17	3	2			22
inframe indel			2			2
splice donor/acceptor (+/-2bp)						0
splice region			1	1		2
non coding			14	6	4	24
Total	28	9	112	40	5

Variants in OTX2

This is a list of pathogenic ClinVar variants found in the OTX2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
14-56800717-A-G		Pituitary hormone deficiency, combined, 6 • Syndromic microphthalmia type 5	Uncertain significance (Jan 15, 2018)
14-56800742-C-G		Pituitary hormone deficiency, combined, 6 • Syndromic microphthalmia type 5	Uncertain significance (Jan 13, 2018)
14-56800769-T-C		Pituitary hormone deficiency, combined, 6 • Retinal dystrophy • Syndromic Microphthalmia, Dominant • OTX2-Related Syndromic Microphthalmia	Benign/Likely benign (Jan 13, 2018)
14-56800802-G-A		Retinal dystrophy • Syndromic microphthalmia type 5 • Syndromic Microphthalmia, Dominant • Pituitary hormone deficiency, combined, 6	Uncertain significance (Jan 13, 2018)
14-56800956-C-T		Syndromic Microphthalmia, Dominant • Syndromic microphthalmia type 5 • Retinal dystrophy • Pituitary hormone deficiency, combined, 6	Benign/Likely benign (Jan 12, 2018)
14-56800971-C-T		Syndromic Microphthalmia, Dominant • Pituitary hormone deficiency, combined, 6 • OTX2-Related Syndromic Microphthalmia • Syndromic microphthalmia type 5	Uncertain significance (Jan 13, 2018)
14-56801068-T-G		Syndromic microphthalmia type 5 • Pituitary hormone deficiency, combined, 6	Uncertain significance (Mar 02, 2018)
14-56801087-G-C		Syndromic microphthalmia type 5 • Retinal dystrophy • Pituitary hormone deficiency, combined, 6 • OTX2-Related Syndromic Microphthalmia	Uncertain significance (Jan 13, 2018)
14-56801087-G-T		Syndromic microphthalmia type 5 • Pituitary hormone deficiency, combined, 6	Uncertain significance (Jan 13, 2018)
14-56801088-T-C		Syndromic Microphthalmia, Dominant • Retinal dystrophy • Pituitary hormone deficiency, combined, 6 • Syndromic microphthalmia type 5	Uncertain significance (Jan 12, 2018)
14-56801161-GAC-G		OTX2-Related Syndromic Microphthalmia • Combined Pituitary Hormone Deficiency, Dominant • Syndromic Microphthalmia, Dominant • Retinal dystrophy	Uncertain significance (Jun 14, 2016)
14-56801192-T-C		Syndromic microphthalmia type 5 • Pituitary hormone deficiency, combined, 6	Uncertain significance (Jan 13, 2018)
14-56801394-TG-T		OTX2-Related Syndromic Microphthalmia • Syndromic Microphthalmia, Dominant • Retinal dystrophy • Combined Pituitary Hormone Deficiency, Dominant	Likely benign (May 14, 2021)
14-56801419-C-T		OTX2-Related Syndromic Microphthalmia • Syndromic Microphthalmia, Dominant • Retinal dystrophy • Pituitary hormone deficiency, combined, 6	Conflicting classifications of pathogenicity (Jan 13, 2018)
14-56801516-C-T		Syndromic microphthalmia type 5 • OTX2-Related Syndromic Microphthalmia • Syndromic Microphthalmia, Dominant • Pituitary hormone deficiency, combined, 6	Uncertain significance (Jan 12, 2018)
14-56801588-C-A		Syndromic microphthalmia type 5 • Pituitary hormone deficiency, combined, 6	Uncertain significance (Jan 13, 2018)
14-56801725-C-T		OTX2-Related Syndromic Microphthalmia • Pituitary hormone deficiency, combined, 6 • not specified • Syndromic microphthalmia type 5 • Retinal dystrophy	Benign/Likely benign (Jan 13, 2018)
14-56801746-G-A			Uncertain significance (Mar 11, 2020)
14-56801756-C-G		Anophthalmia-microphthalmia syndrome	Likely benign (Oct 03, 2023)
14-56801756-C-T		Anophthalmia-microphthalmia syndrome	Likely benign (Jan 02, 2018)
14-56801757-G-A		Anophthalmia-microphthalmia syndrome • Inborn genetic diseases	Uncertain significance (Aug 09, 2021)
14-56801758-A-T		Anophthalmia-microphthalmia syndrome	Uncertain significance (Oct 05, 2023)
14-56801762-T-A		Anophthalmia-microphthalmia syndrome	Likely benign (Jun 30, 2020)
14-56801786-G-T		Anophthalmia-microphthalmia syndrome	Uncertain significance (Dec 13, 2023)
14-56801789-A-G		Pituitary hormone deficiency, combined, 6 • Anophthalmia-microphthalmia syndrome	Benign/Likely benign (Aug 03, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
OTX2	protein_coding	protein_coding	ENST00000339475	3	9773

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.923	0.0765	124669	0	3	124672	0.0000120

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.05	123	160	0.768	0.00000780	1908
Missense in Polyphen		19	54.266	0.35013		658
Synonymous	-0.0999	65	64.0	1.02	0.00000311	616
Loss of Function	3.03	1	12.6	0.0792	6.56e-7	140

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.0000981	0.0000981
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcription factor probably involved in the development of the brain and the sense organs. Can bind to the bicoid/BCD target sequence (BTS): 5'-TCTAATCCC-3'. {ECO:0000269|PubMed:22715480}.
• Disease: DISEASE: Microphthalmia, syndromic, 5 (MCOPS5) [MIM:610125]: Patients manifest unilateral or bilateral microphthalmia/clinical anophthalmia and variable additional features including pituitary dysfunction, coloboma, microcornea, cataract, retinal dystrophy, hypoplasia or agenesis of the optic nerve, agenesis of the corpus callosum, developmental delay, joint laxity, hypotonia, and seizures. Microphthalmia is a disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues (anophthalmia). In many cases, microphthalmia/anophthalmia occurs in association with syndromes that include non-ocular abnormalities. {ECO:0000269|PubMed:15846561, ECO:0000269|PubMed:20396904, ECO:0000269|PubMed:22577225, ECO:0000269|PubMed:24167467}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Pituitary hormone deficiency, combined, 6 (CPHD6) [MIM:613986]: Combined pituitary hormone deficiency is defined as the impaired production of growth hormone and one or more of the other five anterior pituitary hormones. CPHD6 patients manifest neonatal hypoglycemia, and deficiencies of growth hormone, thyroid-stimulating hormone, luteinizing hormone, follicle stimulating hormone and adrenocorticotropic hormone. {ECO:0000269|PubMed:18728160, ECO:0000269|PubMed:22715480}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Retinal dystrophy, early-onset, with or without pituitary dysfunction (RDEOP) [MIM:610125]: An autosomal dominant ocular disease characterized by pattern dystrophy of the retinal pigment epithelium, and photoreceptor degeneration. Mild developmental anomalies include optic nerve head dysplasia, microcornea, and Rathke's cleft cyst. Some patients manifest pituary dysfunction. {ECO:0000269|PubMed:19956411, ECO:0000269|PubMed:25293953}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: TP53 Network;Endoderm Differentiation;Dopaminergic Neurogenesis (Consensus)

Recessive Scores

• pRec: 0.344

Intolerance Scores

• loftool: 0.0813
• rvis_EVS: -0.38
• rvis_percentile_EVS: 27.42

Haploinsufficiency Scores

• pHI: 0.933
• hipred: Y
• hipred_score: 0.851
• ghis: 0.609

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: H
• gene_indispensability_pred: E
• gene_indispensability_score: 0.796

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Otx2
• Phenotype: taste/olfaction phenotype; endocrine/exocrine gland phenotype; growth/size/body region phenotype; homeostasis/metabolism phenotype; cellular phenotype; craniofacial phenotype; digestive/alimentary phenotype; muscle phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); hearing/vestibular/ear phenotype; pigmentation phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; embryo phenotype; skeleton phenotype; vision/eye phenotype

Zebrafish Information Network

• Gene name: otx2b
• Affected structure: ceratobranchial cartilage
• Phenotype tag: abnormal
• Phenotype quality: shortened

Gene ontology

• Biological process: axon guidance;regulation of smoothened signaling pathway;forebrain development;midbrain development;positive regulation of embryonic development;regulation of fibroblast growth factor receptor signaling pathway;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;protein-containing complex assembly;dopaminergic neuron differentiation;primitive streak formation;positive regulation of gastrulation
• Cellular component: nucleus;growth cone;protein-containing complex
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription activator activity, RNA polymerase II-specific;protein binding;eukaryotic initiation factor 4E binding