• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
PITX2 (HGNC:9005) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
paired like homeodomain 2
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
IRID2, IHG2, RIEG, RIEG1, RGS
Alias symbols
IGDS, RS, Brx1, Otlx2, ARP1
%HI
0.8(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.98(Read more about gnomAD pLI score)
LOEUF
0.26(Read more about gnomAD LOEUF score)
Cytoband
4q25
Genomic Coordinates
GRCh37/hg19: chr4:111538579-111563279 NCBI Ensembl UCSC
GRCh38/hg38: chr4:110617423-110642123 NCBI Ensembl UCSC
MANE Select Transcript
NM_000325.6 ENST00000644743.1 (Read more about MANE Select)
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}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-1142
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
10/24/2022

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
HI Evidence:
  • PUBMED: 14630904
    Wang et al (2003) identified a 4bp deletion (NM_153427:c.134_137delACTT) within the PITX2 gene in a three generation Chinese family affected with Rieger syndrome. The identified variant was found to segregate with disease in five affected individuals (dental abnormalities in all and ocular findings in some) and was not observed in any unaffected family members that were tested.
  • PUBMED: 17167399
    Vieira et al (2006) evaluated six unrelated families affected with Axenfeld Rieger syndrome (ARS) for causative variants in the PITX2 gene. Of the four PITX2 variants identified, only one nonsense variant (NM_153427:c.163G>T, p.Glu55Ter) was identified that is expected to undergo nonsense mediated decay (NMD). This variant was found to be de novo in a child with ocular and dental abnormalities consistent with ARS.
  • PUBMED: 20881294
    D'haene et al (2011) screened a cohort of 80 individuals referred for a diagnosis of anterior segment dysgenesis (ASD) to identify causative variants in PITX2 and FOXC1 by sequencing the coding regions of the genes. The authors identified causative variants in 32/80 probands, 13 of which were in the PITX2 gene. Of the PITX2 variants identified, two truncating variants are expected to undergo NMD (one single bp deletion and one nonsense variant) and are included in this curation. The single bp deletion (NM_153427.1:c.137_138del, p.Phe46TyrfsX152) of unknown inheritance was identified in a 9 year old male with ocular and dental abnormalities consistent with ASD. The nonsense variant (NM_153427.1:c.175C>T, p.Gln59X) was determined to be de novo in a male patient with Rieger syndrome.
  • PUBMED: 29939776
    Wang et al (2018) evaluated 20 unrelated patients with ARS for causative variants in PITX2, FOXC1 and PRDM5 by Sanger sequencing and MLPA analysis (for PITX2 and FOXC1). The authors identified potentially causative PITX2 variants in 11/20 probands, the majority of which are truncating variants. Of the truncating variants, four are expected to undergo NMD and are included in this curation (family IDs: QT508, QT421, QT714, QT699). All four probands exhibit ocular and dental abnormalities consistent with ARS and 3/4 additionally were noted to have periumbilical skin. The inheritance pattern in all four individuals is unknown since parents were not tested for the variant, but none of the parents were noted to be affected.
HI Evidence Comments:
Axenfeld-Rieger syndrome (ARS) is a disorder of anterior segment dysgenesis characterized by ocular abnormalities that affect the anterior segment of the eye (including the cornea, iris, lens, trabecular meshwork, and Schlemm canal) and in some cases leads to blindness from glaucoma. Additional systemic abnormalities often associated with this condition include dental anomalies, and redundant umbilical skin. Causative variants in the PITX2 gene are a well established cause of ARS and some variability can be seen in the expressed phenotype of affected individuals. The PITX2 gene encodes a developmental transcription factor that is critical for regulating expression of genes involved in embryogenesis and development of tissues of the anterior segment. The PITX2 gene is relatively small, but many of the critical functional domains are near the C-terminus. Many additional publications exist that described causative truncating PITX2 variants, but given the size of the gene, a large majority may not undergo NMD and without additional functional analysis to demonstrate haploinsufficiency could not be considered for this curation. Tumer et al (2009) and Reis et al (2022) provide excellent summaries of the clinical features ARS patients and mutation spectrum of PITX2 variants and in some cases provide additional information regarding the functional impact of some variants (PMIDs: 19513095, 35882526). While it is unclear if all PITX2 truncating variants result in loss of function (and in some cases could instead result in gain of function), there is sufficient evidence from the curated variants to demonstrate haploinsufficiency as a mechanism of disease for PITX2, which is further validated by a PITX2 heterozygous null mouse model that recapitulates eye and tooth abnormalities consistent with ARS in humans (PMID 10498698).

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)

Genomic View

Select assembly: (NC_000004.11) (NC_000004.12)