PITX2

paired like homeodomain 2, the group of PRD class homeoboxes and pseudogenes

Basic information

Region (hg38): 4:110617422-110642123

Previous symbols: [ "IRID2", "IHG2", "RIEG", "RIEG1", "RGS" ]

Links

ENSG00000164093 ∙ NCBI:5308 ∙ OMIM:601542 ∙ HGNC:9005 ∙ Uniprot:Q99697 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• anterior segment dysgenesis 4 (Definitive), mode of inheritance: AD
• ring dermoid of cornea (Definitive), mode of inheritance: AD
• Axenfeld-Rieger syndrome type 1 (Definitive), mode of inheritance: AD
• Peters anomaly (Definitive), mode of inheritance: AD
• aniridia (Moderate), mode of inheritance: AD
• Axenfeld-Rieger syndrome type 1 (Strong), mode of inheritance: AD
• Axenfeld-Rieger syndrome (Supportive), mode of inheritance: AD
• familial atrial fibrillation (Supportive), mode of inheritance: AD
• ring dermoid of cornea (Supportive), mode of inheritance: AD
• Rieger anomaly (Supportive), mode of inheritance: AD
• Axenfeld anomaly (Supportive), mode of inheritance: AD
• Axenfeld-Rieger syndrome type 1 (Definitive), mode of inheritance: AD
• Axenfeld-Rieger syndrome type 1 (Strong), mode of inheritance: AD
• anterior segment dysgenesis 4 (Strong), mode of inheritance: AD
• Peters anomaly (Limited), mode of inheritance: AD
• ring dermoid of cornea (Limited), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Axenfeld-Rieger syndrome, type 1; Ring dermoid of cornea; Anterior segment dysgenesis 4; Anterior segment dysgenesis 5	AD	Ophthalmologic; Pharmacogenomic	Individuals have a high risk of developing glaucoma, but treatment may not be effective in the majority of cases; Agents that may contribute to glaucoma should be avoided	Dental; Ophthalmologic	4953922; 6029228; 6871144; 2594319; 7581385; 8944018; 9437321; 9618168; 10051017; 11004268; 11929847; 12015277; 15591271; 17197537; 22569110
Severe and difficult to treat glaucoma has been reported in many individuals with Anterior segment dysgenesis

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PITX2 gene.

• Axenfeld-Rieger syndrome type 1 (71 variants)
• not provided (53 variants)
• Ring dermoid of cornea (44 variants)
• Cataract (43 variants)
• PITX2-Related Eye Abnormalities (43 variants)
• Irido-corneo-trabecular dysgenesis (43 variants)
• Hypoplasia of the iris (41 variants)
• Anterior segment dysgenesis 4 (38 variants)
• Axenfeld-Rieger syndrome type 1;Anterior segment dysgenesis 4 (32 variants)
• not specified (9 variants)
• Anterior segment dysgenesis 1 (9 variants)
• Anterior segment dysgenesis 4;Axenfeld-Rieger syndrome type 1 (9 variants)
• Inborn genetic diseases (8 variants)
• PITX2-related condition (3 variants)
• Axenfeld-Rieger syndrome (2 variants)
• Axenfeld-Rieger anomaly with partially absent eye muscles, distinctive face, hydrocephaly, and skeletal abnormalities (1 variants)
• Atrial fibrillation, familial, 1 (1 variants)
• Lung adenocarcinoma (1 variants)
• Rieger anomaly (1 variants)
• Anterior segment dysgenesis (1 variants)
• Pituitary stalk interruption syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PITX2 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			4	10	1	15
missense	5	9	17	2		33
nonsense	11	2	1			14
start loss						0
frameshift	14	2				16
inframe indel						0
splice donor/acceptor (+/-2bp)	3	1				4
splice region			3	2	2	7
non coding	1		26	12	19	58
Total	34	14	48	24	20

Variants in PITX2

This is a list of pathogenic ClinVar variants found in the PITX2 region.

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

Position	Type	Phenotype	Significance	ClinVar
4-110617429-T-G		Irido-corneo-trabecular dysgenesis • Cataract • Axenfeld-Rieger syndrome type 1 • Anterior segment dysgenesis 4 • Hypoplasia of the iris • PITX2-Related Eye Abnormalities • Ring dermoid of cornea	Uncertain significance (Jan 13, 2018)
4-110617438-T-C		Hypoplasia of the iris • Cataract • Anterior segment dysgenesis 4 • Irido-corneo-trabecular dysgenesis • Ring dermoid of cornea • Axenfeld-Rieger syndrome type 1 • PITX2-Related Eye Abnormalities	Uncertain significance (Jan 13, 2018)
4-110617514-T-C		Anterior segment dysgenesis 4 • PITX2-Related Eye Abnormalities • Hypoplasia of the iris • Axenfeld-Rieger syndrome type 1 • Cataract • Ring dermoid of cornea • Irido-corneo-trabecular dysgenesis	Uncertain significance (Jan 13, 2018)
4-110617553-A-G		Irido-corneo-trabecular dysgenesis • Hypoplasia of the iris • Axenfeld-Rieger syndrome type 1 • Anterior segment dysgenesis 4 • Cataract • Ring dermoid of cornea • PITX2-Related Eye Abnormalities	Uncertain significance (Jan 13, 2018)
4-110617603-A-G		Irido-corneo-trabecular dysgenesis • Cataract • Hypoplasia of the iris • Ring dermoid of cornea • Anterior segment dysgenesis 4 • Axenfeld-Rieger syndrome type 1 • PITX2-Related Eye Abnormalities	Uncertain significance (Jan 13, 2018)
4-110617654-C-T		Anterior segment dysgenesis 4 • Cataract • Hypoplasia of the iris • Irido-corneo-trabecular dysgenesis • PITX2-Related Eye Abnormalities • Axenfeld-Rieger syndrome type 1 • Ring dermoid of cornea	Benign/Likely benign (Jun 01, 2021)
4-110617671-G-A		Anterior segment dysgenesis 1 • PITX2-Related Eye Abnormalities • Cataract • Ring dermoid of cornea • Irido-corneo-trabecular dysgenesis • Axenfeld-Rieger syndrome type 1 • Hypoplasia of the iris	Benign (May 14, 2021)
4-110617685-G-A		Anterior segment dysgenesis 4 • PITX2-Related Eye Abnormalities • Hypoplasia of the iris • Axenfeld-Rieger syndrome type 1 • Irido-corneo-trabecular dysgenesis • Cataract • Ring dermoid of cornea	Uncertain significance (Feb 02, 2018)
4-110617746-TAAC-T		Anterior segment dysgenesis 1 • Cataract • Ring dermoid of cornea • Axenfeld-Rieger syndrome • Anterior segment dysgenesis 4 • PITX2-Related Eye Abnormalities • Irido-corneo-trabecular dysgenesis	Uncertain significance (Jun 14, 2016)
4-110617755-C-G		Irido-corneo-trabecular dysgenesis • Hypoplasia of the iris • Ring dermoid of cornea • Cataract • Anterior segment dysgenesis 4 • PITX2-Related Eye Abnormalities • Axenfeld-Rieger syndrome type 1	Uncertain significance (Jan 13, 2018)
4-110617785-T-C		Irido-corneo-trabecular dysgenesis • PITX2-Related Eye Abnormalities • Cataract • Ring dermoid of cornea • Hypoplasia of the iris • Anterior segment dysgenesis 4 • Axenfeld-Rieger syndrome type 1	Conflicting classifications of pathogenicity (Jan 13, 2018)
4-110617861-T-G		Hypoplasia of the iris • Cataract • Ring dermoid of cornea • Axenfeld-Rieger syndrome type 1 • Irido-corneo-trabecular dysgenesis • PITX2-Related Eye Abnormalities • Anterior segment dysgenesis 1	Uncertain significance (Jan 13, 2018)
4-110617949-T-A		PITX2-Related Eye Abnormalities • Hypoplasia of the iris • Cataract • Ring dermoid of cornea • Irido-corneo-trabecular dysgenesis • Axenfeld-Rieger syndrome type 1 • Anterior segment dysgenesis 4	Uncertain significance (Jan 12, 2018)
4-110617952-C-T		Anterior segment dysgenesis 4 • Irido-corneo-trabecular dysgenesis • PITX2-Related Eye Abnormalities • Hypoplasia of the iris • Ring dermoid of cornea • Cataract • Axenfeld-Rieger syndrome type 1	Uncertain significance (Jan 13, 2018)
4-110618006-A-T		PITX2-Related Eye Abnormalities • Anterior segment dysgenesis 1 • Axenfeld-Rieger syndrome type 1 • Irido-corneo-trabecular dysgenesis • Hypoplasia of the iris • Cataract • Ring dermoid of cornea	Uncertain significance (Jan 12, 2018)
4-110618018-T-G		Ring dermoid of cornea • Anterior segment dysgenesis 4 • Irido-corneo-trabecular dysgenesis • Hypoplasia of the iris • Cataract • PITX2-Related Eye Abnormalities • Axenfeld-Rieger syndrome type 1	Uncertain significance (Jan 13, 2018)
4-110618142-C-T		Inborn genetic diseases	Uncertain significance (Nov 21, 2022)
4-110618159-C-T		Anterior segment dysgenesis 4;Axenfeld-Rieger syndrome type 1 • Inborn genetic diseases	Uncertain significance (Aug 19, 2021)
4-110618171-G-T		PITX2-related disorder	Uncertain significance (Jan 26, 2024)
4-110618173-C-T		Axenfeld-Rieger syndrome type 1;Anterior segment dysgenesis 4	Likely benign (Jun 17, 2022)
4-110618184-C-T		Axenfeld-Rieger syndrome type 1;Anterior segment dysgenesis 4	Uncertain significance (May 16, 2022)
4-110618198-A-C			Uncertain significance (Sep 16, 2018)
4-110618210-TGCTTTGCTTTCAGTCTCAGGCTG-T		Axenfeld-Rieger syndrome type 1	Pathogenic (Jun 23, 2022)
4-110618238-G-A		Ring dermoid of cornea • Axenfeld-Rieger syndrome type 1 • Anterior segment dysgenesis 4 • PITX2-Related Eye Abnormalities • Cataract • Irido-corneo-trabecular dysgenesis • Hypoplasia of the iris • Axenfeld-Rieger syndrome type 1;Anterior segment dysgenesis 4	Conflicting classifications of pathogenicity (Jan 02, 2024)
4-110618260-AT-A		Axenfeld-Rieger anomaly with partially absent eye muscles, distinctive face, hydrocephaly, and skeletal abnormalities	Pathogenic (Oct 15, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PITX2	protein_coding	protein_coding	ENST00000306732	3	24701

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.976	0.0238	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.55	124	183	0.678	0.00000839	2102
Missense in Polyphen		45	78.357	0.57429		913
Synonymous	-0.668	87	79.4	1.10	0.00000386	653
Loss of Function	3.14	0	11.5	0.00	5.01e-7	123

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	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Controls cell proliferation in a tissue-specific manner and is involved in morphogenesis. During embryonic development, exerts a role in the expansion of muscle progenitors. May play a role in the proper localization of asymmetric organs such as the heart and stomach. Isoform PTX2C is involved in left-right asymmetry the developing embryo (By similarity). {ECO:0000250}.
• Disease: DISEASE: Axenfeld-Rieger syndrome 1 (RIEG1) [MIM:180500]: An autosomal dominant disorder of morphogenesis that results in abnormal development of the anterior segment of the eye, and results in blindness from glaucoma in approximately 50% of affected individuals. Additional features include aniridia, maxillary hypoplasia, hypodontia, anal stenosis, redundant periumbilical skin. {ECO:0000269|PubMed:10937553, ECO:0000269|PubMed:11487566, ECO:0000269|PubMed:12381896, ECO:0000269|PubMed:16936096, ECO:0000269|PubMed:8944018}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Anterior segment dysgenesis 4 (ASGD4) [MIM:137600]: A form of anterior segment dysgenesis, a group of defects affecting anterior structures of the eye including cornea, iris, lens, trabecular meshwork, and Schlemm canal. Anterior segment dysgeneses result from abnormal migration or differentiation of the neural crest derived mesenchymal cells that give rise to components of the anterior chamber during eye development. Different anterior segment anomalies may exist alone or in combination, including iris hypoplasia, enlarged or reduced corneal diameter, corneal vascularization and opacity, posterior embryotoxon, corectopia, polycoria, abnormal iridocorneal angle, ectopia lentis, and anterior synechiae between the iris and posterior corneal surface. Clinical conditions falling within the phenotypic spectrum of anterior segment dysgeneses include aniridia, Axenfeld anomaly, Reiger anomaly/syndrome, Peters anomaly, and iridogoniodysgenesis. ASGD4 is an autosomal dominant disease. {ECO:0000269|PubMed:10051017, ECO:0000269|PubMed:20881294, ECO:0000269|PubMed:9437321, ECO:0000269|PubMed:9618168}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ring dermoid of cornea (RDC) [MIM:180550]: An ocular disorder characterized by bilateral annular limbal dermoids (growths with a skin-like structure) with corneal and conjunctival extension. {ECO:0000269|PubMed:15591271, ECO:0000269|PubMed:22224469}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: TGF-beta signaling pathway - Homo sapiens (human);WNT-Ncore;Heart Development;Mesodermal Commitment Pathway;BMP Signaling Pathway in Eyelid Development;Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors;Gene expression (Transcription);multi-step regulation of transcription by pitx2;Generic Transcription Pathway;RNA Polymerase II Transcription;TFAP2 (AP-2) family regulates transcription of other transcription factors;Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors;Regulation of nuclear beta catenin signaling and target gene transcription (Consensus)

Recessive Scores

• pRec: 0.635

Intolerance Scores

• loftool: 0.0743
• rvis_EVS: -0.34
• rvis_percentile_EVS: 30.37

Haploinsufficiency Scores

• pHI: 0.988
• hipred: Y
• hipred_score: 0.875
• ghis: 0.540

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.997

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pitx2
• Phenotype: endocrine/exocrine gland phenotype; growth/size/body region phenotype; homeostasis/metabolism phenotype; cellular phenotype; craniofacial phenotype; muscle phenotype; digestive/alimentary 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); limbs/digits/tail phenotype; pigmentation phenotype; hematopoietic system 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); 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); normal phenotype; reproductive system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; liver/biliary system phenotype; embryo phenotype; skeleton phenotype; immune system phenotype; vision/eye phenotype

Zebrafish Information Network

• Gene name: pitx2
• Affected structure: endodermal cell
• Phenotype tag: abnormal
• Phenotype quality: movement quality

Gene ontology

• Biological process: cardiac neural crest cell migration involved in outflow tract morphogenesis;regulation of transcription, DNA-templated;regulation of transcription by RNA polymerase II;determination of left/right symmetry;anatomical structure morphogenesis;hair cell differentiation;deltoid tuberosity development;odontogenesis;camera-type eye development;positive regulation of transcription by RNA polymerase II;spleen development;somatotropin secreting cell differentiation;prolactin secreting cell differentiation;iris morphogenesis;cell proliferation involved in outflow tract morphogenesis;left/right axis specification
• Cellular component: nucleus;nucleoplasm;transcription factor complex
• Molecular function: transcription regulatory region sequence-specific DNA binding;RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;RNA polymerase II transcription factor binding;RNA polymerase II activating transcription factor binding;DNA-binding transcription factor activity;protein binding;transcription factor binding;sequence-specific DNA binding